bims-hafaim 2021-09-19 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–09–19
twenty-two papers selected by
Kyle McCommis, Saint Louis University

Why the diabetic heart is energy inefficient: A ketogenesis and ketolysis perspective.
TFEB Insufficiency Promotes Cardiac Hypertrophy by Blocking Autophagic Degradation of GATA4.
Empagliflozin maintains capillarization and improves cardiac function in a murine model of left ventricular pressure overload.
Cardiac PANK1 Deletion Exacerbates Ventricular Dysfunction During Pressure Overload.
Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure.
Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism.
Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice.
Overview of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors for the Treatment of Non-diabetic Heart Failure Patients.
Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling.
Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction.
Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart.
UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II-Induced Hypertension.
Spatiotemporal AMPKα2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only.
Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II - induced cardiac hypertrophy and vascular remodeling.
Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.
SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled?
GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.
[Effect of neuregulin-1 on cardiac glucose metabolism in rats with experimental myocardial infarction].
GLP-1 receptor agonist treatment of high-carbohydrate intake-induced metabolic syndrome provides pleiotropic effects on cardiac dysfunction through alleviations in electrical and intracellular Ca2+ abnormalities and mitochondrial dysfunction.
Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats.
Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure.
Phosphoproteomics analysis of diabetic cardiomyopathy in aging-accelerated mice and effects of D-Pinitol.

Am J Physiol Heart Circ Physiol. 2021 Sep 17.

Why the diabetic heart is energy inefficient: A ketogenesis and ketolysis perspective.

Paras Kumar Mishra.

  Lack of glucose uptake compromises metabolic flexibility and reduces energy efficiency in the diabetes mellitus (DM) heart. Although increased utilization of fatty acid to compensate glucose substrate has been studied, less is known about ketone body metabolism in the DM heart. Ketogenic diet reduces obesity, a risk factor for T2DM. How ketogenic diet affects ketone metabolism in the DM heart remains unclear. At the metabolic level, the DM heart differs from the non-DM heart due to altered metabolic substrate and the T1DM heart differs from the T2DM heart due to insulin levels. How these changes affect ketone body metabolism in the DM heart are poorly understood. Ketogenesis produces ketone bodies by utilizing acetyl CoA whereas ketolysis consumes ketone bodies to produce acetyl CoA, showing their opposite roles in the ketone body metabolism. Cardiac-specific transgenic upregulation of ketogenesis enzyme or knockout of ketolysis enzyme causes metabolic abnormalities leading to cardiac dysfunction. Empirical evidence demonstrates upregulated transcription of ketogenesis enzymes, no change in the levels of ketone body transporters, very high levels of ketone bodies, and reduced expression and activity of ketolysis enzymes in the T1DM heart. Based on these observations, I hypothesize that increased transcription and activity of cardiac ketogenesis enzyme suppresses ketolysis enzymes in the DM heart, which decreases cardiac energy efficiency. The T1DM heart exhibits highly upregulated ketogenesis compared to T2DM due to lack of insulin that inhibits ketogenesis enzyme.

Keywords:  Randle cycle; insulin; ketogenic diet; ketone body; metabolism

DOI:  https://doi.org/10.1152/ajpheart.00260.2021
J Biol Chem. 2021 Sep 10. pii: S0021-9258(21)00991-1. [Epub ahead of print] 101189

TFEB Insufficiency Promotes Cardiac Hypertrophy by Blocking Autophagic Degradation of GATA4.

Rui Song, Han Lei, Li Feng, Wanwen Cheng, Ying Li, Ling Ling Yao, Jie Liu.

  Autophagosome-lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found TFEB was significantly decreased, while autophagosome markers were increased in phenylephrine (PE)- and transverse aortic constriction (TAC)-induced cardiomyocyte hypertrophy and failing hearts from patients with dilated cardiomyopathy. Knocking down TFEB induced ALP insufficiency, as indicated by increased autophagosome markers, decreased LC3II flux, and cardiomyocyte hypertrophy manifested through increased levels of atrial natriuretic peptide (ANP) and β-myosin heavy chain 7 (β-MHC) and enlarged cell size. The effects of TFEB knockdown were abolished by promoting autophagy. TFEB overexpression improved autophagic flux and attenuated PE-stimulated cardiomyocyte hypertrophy and TAC-induced hypertrophic remodeling, fibrosis, and cardiac dysfunction. Curcumin analog compound C1, a specific TFEB activator, similarly attenuated PE-induced ALP insufficiency and cardiomyocyte hypertrophy. TFEB knockdown increased the accumulation of GATA4, a transcription factor for several genes causing cardiac hypertrophy by blocking autophagic degradation of GATA4, whereas knocking down GATA4 attenuated TFEB downregulation-induced cardiomyocyte hypertrophy. Both TFEB overexpression and C1 promoted GATA4 autophagic degradation and alleviated PE-induced cardiomyocyte hypertrophy. In conclusion, TFEB downregulation plays a vital role in the development of pressure overload-induced cardiac hypertrophy by causing ALP insufficiency and blocking autophagic degradation. Activation of TFEB represents a potential therapeutic strategy for treating cardiac hypertrophy.

Keywords:  GATA4; TFEB; autophagosome-lysosome pathway; autophagy; heart; hypertrophy

DOI:  https://doi.org/10.1016/j.jbc.2021.101189
Sci Rep. 2021 Sep 15. 11(1): 18384

Empagliflozin maintains capillarization and improves cardiac function in a murine model of left ventricular pressure overload.

Masaaki Nakao, Ippei Shimizu, Goro Katsuumi, Yohko Yoshida, Masayoshi Suda, Yuka Hayashi, Ryutaro Ikegami, Yung Ting Hsiao, Shujiro Okuda, Tomoyoshi Soga, Tohru Minamino.

Patients with type 2 diabetes treated with Sodium glucose transporter 2 (SGLT2) inhibitors show reduced mortality and hospitalization for heart failure (HF). SGLT2 inhibitors are considered to activate multiple cardioprotective pathways; however, underlying mechanisms are not fully described. This study aimed to elucidate the underlying mechanisms of the beneficial effects of SGLT2 inhibitors on the failing heart. We generated a left ventricular (LV) pressure overload model in C57BL/6NCrSlc mice by transverse aortic constriction (TAC) and examined the effects of empagliflozin (EMPA) in this model. We conducted metabolome and transcriptome analyses and histological and physiological examinations. EMPA administration ameliorated pressure overload-induced systolic dysfunction. Metabolomic studies showed that EMPA increased citrulline levels in cardiac tissue and reduced levels of arginine, indicating enhanced metabolism from arginine to citrulline and nitric oxide (NO). Transcriptome suggested possible involvement of the insulin/AKT pathway that could activate NO production through phosphorylation of endothelial NO synthase (eNOS). Histological examination of the mice showed capillary rarefaction and endothelial apoptosis after TAC, both of which were significantly improved by EMPA treatment. This improvement was associated with enhanced expression phospho-eNOS and NO production in cardiac endothelial cells. NOS inhibition attenuated these cardioprotective effects of EMPA. The in vitro studies showed that catecholamine-induced endothelial apoptosis was inhibited by NO, arginine, or AKT activator. EMPA activates the AKT/eNOS/NO pathway, which helps to suppress endothelial apoptosis, maintain capillarization and improve systolic dysfunction during LV pressure overload.

DOI: https://doi.org/10.1038/s41598-021-97787-2
Am J Physiol Heart Circ Physiol. 2021 Sep 17.

Cardiac PANK1 Deletion Exacerbates Ventricular Dysfunction During Pressure Overload.

Timothy N Audam, Caitlin M Howard, Lauren F Garrett, Yi Wei Zheng, James A Bradley, Kenneth R Brittian, Matthew W Frank, Kyle L Fulghum, Miklós Pólos, Szilvia Herczeg, Béla Merkely, Tamás Radovits, Shizuka Uchida, Bradford G Hill, Sujith Dassanayaka, Suzanne Jackowski, Steven P Jones.

  Coenzyme A (CoA) is an essential co-factor required for intermediary metabolism. Perturbations in homeostasis of CoA have been implicated in various pathologies; however, whether CoA homeostasis is changed and the extent to which CoA levels contribute to ventricular function and remodeling during pressure overload has not been explored. In this study, we sought to assess changes in CoA biosynthetic pathway during pressure overload and determine the impact of limiting CoA on cardiac function. We limited cardiac CoA levels by deleting the rate limiting enzyme in CoA biosynthesis, Pank1. We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1-/-) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared to Pank1 sufficient littermates (cmPank1+/+) but exerted no obvious deleterious impact on the mice at baseline. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, there was more ventricular dilation in cmPank1-/- during pressure overload. To explore potential mechanisms contributing to this phenotype, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Collectively, our study underscores the role of elevated CoA levels in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart.

Keywords:  CoA; fibrosis; heart failure; metabolism; pantothenate kinase

DOI:  https://doi.org/10.1152/ajpheart.00411.2021
Annu Rev Pharmacol Toxicol. 2021 Sep 13.

Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure.

Kevin S Shah, James C Fang.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve blood glucose control by blocking renal glucose reabsorption with little subsequent risk of hypoglycemia. Consequently, there are decreases in plasma volume, body weight, and blood pressure. Additional putative benefits include improved cardiovascular energetics, decreased systemic inflammation, and less renal dysfunction. Multiple cardiovascular outcome trials in diabetic patients have demonstrated this drug class reduces the risk of adverse cardiovascular events. Reductions in heart failure (HF) hospitalization suggested that SGLT2 inhibitors might prove useful for the primary treatment of HF. Two large subsequent trials studying SGLT2 inhibitors in heart failure with reduced ejection fraction (HFrEF) demonstrated a reduction in cardiovascular mortality, HF hospitalizations, and renal-specific adverse events. This medication class is now recognized as a new pillar of therapy for patients with HFrEF. The cardiovascular and HF community await the results of ongoing trials of SGLT2 inhibition in patients with HF with preserved ejection fraction. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pharmtox-052120-014725
Acta Pharmacol Sin. 2021 Sep 14.

Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism.

Fan Qiu, Yi Yuan, Wei Luo, Yan-Shan Gong, Zhong-Ming Zhang, Zhong-Min Liu, Ling Gao.

  Myocardial infarction (MI) causes disturbances in myocardial energy metabolism, ultimately leading to a poor prognosis. Cytosolic glycogen autophagy (glycophagy) and mitochondrial autophagy (mitophagy) are upregulated in MI to optimize energy metabolism but to a limited extent. Asiatic acid (AA), a pentacyclic triterpene derived from the traditional Chinese herb Centella asiatica, displays anti-inflammatory, antioxidant, and antiapoptotic activities. AA has been found to alleviate focal cerebral and liver ischemic injury by reversing mitochondrial dysfunction. In this study, we investigated whether AA exerted cardioprotective effects against MI by activating glycophagy and mitophagy to improve the energy balance. In vitro cardioprotective effects were examined in neonatal mouse cardiomyocytes subjected to oxygen-glucose deprivation for 12 h. Treatment with AA (2-50 μM) significantly increased cell viability and improved the energy metabolism evidenced by increased ATP level and phosphocreatine/ATP ratio. In vivo cardioprotective effects were studied in a mouse model of MI. Administration of AA (5-125 mg·kg-1·d-1, ig) significantly reduced infarct size and ischemic myocardial injury, and improved cardiac function. AA treatment also promoted mitophagy and relieved mitochondrial edema evidenced by increased number of mitophagosomes in ischemic myocardium in vivo and increased mitochondria-light chain 3 (LC3)-II colocalization in ODG-treated cardiomyocytes in vitro. Mitophagy activation was accompanied by activation of the AMPK signaling pathway. Knockdown of AMPK abolished AA-activated mitophagy. Furthermore, we showed that glycophagy was upregulated in OGD cardiomyocytes evidenced by increased starch binding domain protein 1 (STBD1)-GABA type A receptor-associated protein-like 1(GABARAPL1) interaction and extracellular acidification rate, whereas AA treatment further promoted glycophagy accompanied by PI3K/Akt activation. PI3K inhibitor LY294002 or Akt inhibitor GSK690693 blocked the effects of AA on glycophagy and glycolysis. Finally, simultaneous inhibition of glycophagy and mitophagy abolished the cardioprotective effects and energy regulation of AA. These results demonstrate that AA protects ischemic cardiomyocytes by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/Akt and AMPK pathways.

Keywords:  AMPK signaling; asiatic acid; energy metabolism; glycophagy; mitophagy; myocardial infarction

DOI:  https://doi.org/10.1038/s41401-021-00763-9
Theranostics. 2021 ;11(18): 8993-9008

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice.

Wei Wu, Mark Ziemann, Kevin Huynh, Gang She, Zheng-Da Pang, Yi Zhang, Thy Duong, Helen Kiriazis, Tian-Tian Pu, Ru-Yue Bai, Jing-Jing Li, Yu Zhang, Ming-Xia Chen, Junichi Sadoshima, Xiu-Ling Deng, Peter J Meikle, Xiao-Jun Du.

  Rationale: Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM). Methods: Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed. Results: In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets. Conclusion: Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.

Keywords:  Hippo pathway; dilated cardiomyopathy; heart failure; mitochondria; transcriptome analysis

DOI:  https://doi.org/10.7150/thno.62302
Cureus. 2021 Aug;13(8): e17118

Overview of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors for the Treatment of Non-diabetic Heart Failure Patients.

Irina Balan, Tetyana Khayo, Sevara Sultanova, Yuliia Lomakina.

  Heart failure (HF) is a clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood, and results in low life quality and expectancy, creating a significant burden on the healthcare system. The pharmacological HF management has remained unchanged for a decade, however, several randomized clinical trials have demonstrated the potential clinical benefits of sodium-glucose cotransporter-2 inhibitors, an antidiabetic agent, by reducing the rate of hospitalizations for HF, cardiovascular death, and all-cause death. The cardioprotective effects are characterized by reduction of inflammatory, metabolic and ionic dyshomeostasis despite the diabetic status. Since the United States Food and Drug Administration (FDA) approval in May 2020, SGLT2 inhibitors have been used mostly in heart failure with reduced ejection fraction (HFrEF). In this review article, we provide a comprehensive overview of the potential benefits, effectiveness, and safety profile of SGLT2 inhibitors used in HF patients with no history of diabetes mellitus.

Keywords:  a sodium-glucose cotransporter 2 inhibitor; canagliflozin; cardiovascular outcomes trials; chronic heart failure; dapagliflozin; empagliflozin

DOI:  https://doi.org/10.7759/cureus.17118
Pharmacology. 2021 Sep 08. 1-15

Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling.

Yong Chen, Ting He, Zhongjun Zhang, Junzhi Zhang.

   INTRODUCTION: Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms.
METHODS: In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques.
RESULTS: In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression.
CONCLUSIONS: Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

Keywords:  Cardiac hypertrophy; Pressure overload; Resveratrol; Silent information regulator 1; Transforming growth factor-β1

DOI:  https://doi.org/10.1159/000518464
Can Fam Physician. 2021 09;67(9): 678

Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction.

Jamie Falk, Jennifer Potter, Ricky D Turgeon.

DOI: https://doi.org/10.46747/cfp.6709678
Diabetes. 2021 Sep 15. pii: db210398. [Epub ahead of print]

Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart.

Maria da Luz Sousa Fialho, Ujang Purnama, Kaitlyn Mjh Dennis, Claudia N Montes Aparicio, Marcos Castro-Guarda, Emmanuelle Massourides, Damian J Tyler, Carolyn A Carr, Lisa C Heather.

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart.In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment.In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.

DOI: https://doi.org/10.2337/db21-0398
J Am Heart Assoc. 2021 Sep 17. e022556

UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II-Induced Hypertension.

Xu Chen, Sadia Ashraf, Nadia Ashraf, Romain Harmancey.

  Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3+/-) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3+/- rats and ucp3+/+ littermates fed a high-salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e'; 18.8±1.0 versus 14.9±0.6; P<0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P<0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P<0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II-treated ucp3+/- rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.

Keywords:  diastolic function; hypertension; obesity; oxidative stress; uncoupling protein

DOI:  https://doi.org/10.1161/JAHA.121.022556
Biol Sex Differ. 2021 Sep 17. 12(1): 52

Spatiotemporal AMPKα2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only.

Lucile Grimbert, Maria-Nieves Sanz, Mélanie Gressette, Catherine Rucker-Martin, Marta Novotova, Audrey Solgadi, Ahmed Karoui, Susana Gomez, Kaveen Bedouet, Eric Jacquet, Christophe Lemaire, Vladimir Veksler, Mathias Mericskay, Renée Ventura-Clapier, Jérôme Piquereau, Anne Garnier.

   BACKGROUND: The AMP-activated protein kinase (AMPK) is a major regulator of cellular energetics which plays key role in acute metabolic response and in long-term adaptation to stress. Recent works have also suggested non-metabolic effects.
METHODS: To decipher AMPK roles in the heart, we generated a cardio-specific inducible model of gene deletion of the main cardiac catalytic subunit of AMPK (Ampkα2) in mice. This allowed us to avoid the eventual impact of AMPK-KO in peripheral organs.
RESULTS: Cardio-specific Ampkα2 deficiency led to a progressive left ventricular systolic dysfunction and the development of cardiac fibrosis in males. We observed a reduction in complex I-driven respiration without change in mitochondrial mass or in vitro complex I activity, associated with a rearrangement of the cardiolipins and reduced integration of complex I into the electron transport chain supercomplexes. Strikingly, none of these defects were present in females. Interestingly, suppression of estradiol signaling by ovariectomy partially mimicked the male sensitivity to AMPK loss, notably the cardiac fibrosis and the rearrangement of cardiolipins, but not the cardiac function that remained protected.
CONCLUSION: Our results confirm the close link between AMPK and cardiac mitochondrial function, but also highlight links with cardiac fibrosis. Importantly, we show that AMPK is differently involved in these processes in males and females, which may have clinical implications for the use of AMPK activators in the treatment of heart failure.

Keywords:  AMP-activated protein kinase; Cardiolipins; Energy metabolism; Fibrosis; Heart

DOI:  https://doi.org/10.1186/s13293-021-00394-z
Am J Physiol Heart Circ Physiol. 2021 Sep 17.

Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II - induced cardiac hypertrophy and vascular remodeling.

Irakli Kopaliani, Natalia Jarzebska, Silke Brilloff, Anne Kolouschek, Jens Martens-Lobenhoffer, Stefan R Bornstein, Stefanie M Bode-Böger, Vinitha N Ragavan, Norbert Weiss, Arduino A Mangoni, Andreas Deussen, Roman N Rodionov.

   BACKGROUND: Cardiovascular complications are the leading cause of death and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from Ang II-induced end organ damage.
METHODS AND RESULTS: Angiotensin II (ANGII) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (TG) and wild type (WT) littermates for two or four weeks. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure (SBP) was measured weekly and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after one week of ANGII infusion was not different between the groups, while TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 weeks of ANGII infusion in the high dose and after 4 weeks in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross sectional area and less interstitial fibrosis as compared to WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2 and showed better endothelium-dependent relaxation.
CONCLUSIONS: We demonstrated that overexpression of DDAH1 protects from ANGII-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.

Keywords:  angiotensin II; cardiac remodeling; dimethylarginine dimethylaminohydrolase 1; hypertension; vascular remodeling

DOI:  https://doi.org/10.1152/ajpheart.00064.2021
J Am Heart Assoc. 2021 Sep 13. e019918

Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.

Ayodele Odutayo, Bruno R da Costa, Tiago V Pereira, Vinay Garg, Samir Iskander, Fatimah Roble, Rahim Lalji, Cesar A Hincapié, Aquila Akingbade, Myanca Rodrigues, Arnav Agarwal, Bishoy Lawendy, Pakeezah Saadat, Jacob A Udell, Francesco Cosentino, Peter J Grant, Subodh Verma, Peter Jüni.

  Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Keywords:  heart failure; ischemic stroke; meta‐analysis; myocardial infarction; type 2 diabetes

DOI:  https://doi.org/10.1161/JAHA.120.019918
Curr Heart Fail Rep. 2021 Sep 15.

SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled?

Steffen Pabel, Nazha Hamdani, Mark Luedde, Samuel Sossalla.

   PURPOSE OF REVIEW: SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms.
RECENT FINDINGS: Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

Keywords:  HFpEF; HFrEF; Heart failure; SGLT2 inhibitors

DOI:  https://doi.org/10.1007/s11897-021-00529-8
Cardiovasc Diabetol. 2021 Sep 15. 20(1): 189

GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.

Dario Giugliano, Lorenzo Scappaticcio, Miriam Longo, Paola Caruso, Maria Ida Maiorino, Giuseppe Bellastella, Antonio Ceriello, Paolo Chiodini, Katherine Esposito.

   BACKGROUND: A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM).
METHODS: We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease).
RESULTS: GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001).
CONCLUSIONS: GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Keywords:  Albiglutide; Cardiorenal outcomes; Cardiovascular outcome trials; Dulaglutide; Efpeglenatide; Exenatide; GLP-1RA; Liraglutide; Lixisenatide; Oral semaglutide; Semaglutide; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-021-01366-8
Zhonghua Xin Xue Guan Bing Za Zhi. 2021 Sep 24. 49(9): 912-919

[Effect of neuregulin-1 on cardiac glucose metabolism in rats with experimental myocardial infarction].

J F Wang, F H Li, D L Shen, Y Song, Y Y Wang, J M Zhou, J B Ge.

Objective: To investigate the effect of neuregulin-1(NRG-1) on cardiac glucose metabolism in Sprague Dawley (SD) rats with experimental myocardial infarction (MI). Methods: Adult male SD rats were randomly divided into three groups: the sham-operated group, MI group, and MI+NRG1 group. The rat MI model was established via ligation of the left anterior descending coronary artery. Two weeks after operation, echocardiography was performed, MI rats with left ventricular ejection fraction (LVEF) between 0.3-0.5 were selected and randomly assigned to MI group and MI+NRG-1 group. Rats in MI+NRG-1 group were treated with recombinant human NRG-1β (100 μg/kg) via tail vein at 2 weeks after operation (twice per week for 6 weeks); while rats in sham-operated group and MI group received equal volume of physiological saline. By the end of administration, echocardiography and small animal positron emission tomography (PET) were performed to detect cardiac function and myocardial glucose uptake. Myocardial morphology and collagen volume fraction, cardiomyocyte apoptosis and reactive oxygen species (ROS) production were evaluated by histopathologic analysis. Myocardial pyruvate dehydrogenase (PDH) and citrate synthase (CS) activity, as well as ATP production were detected by commercial kits. The mRNA and protein expression levels of NRG-1, p-ErbB4, and key factors involved in glucose metabolism (including Glut-4, HK2, PDK4, PDH, CS) were detected by quantitative real-time PCR (qRT-PCR) and Western blot assay, respectively. Results: With the MI model successfully established, the left ventricular ejection fraction(LVEF) and left ventricular shortening fraction(LVFS) were significantly lower in MI group and MI+NRG-1 group than that in sham group (both P<0.01), while there was no significant difference between MI group and MI+NRG-1 group(all P>0.05). After 6 weeks of NRG-1β intervention, the LVEF and LVFS were significantly higher in MI+NRG-1 group than in MI group (both P<0.01). By the end of experiment, PET imaging showed that the mean standardized uptake value (SUVmean) were lower in MI+NRG-1 group than in the sham group (4.06±0.28 vs. 5.18±0.37, P<0.01), while significantly higher than that in MI group (4.06±0.28 vs.2.86±0.49, P<0.01). Histopathological analysis showed that compared with MI group, rats in MI+NRG-1 group exhibited significantly decreased left ventricle collagen volume fraction ((7.83±1.24) % vs. (18.31±3.58) %, P<0.01), cardiomyocyte apoptosis((37.98±4.26)% vs. (67.04±5.38)%, P<0.01), and DHE fluorescence intensity(0.057 28±0.007 06 vs. 0.076 94±0.008 46, P<0.01), indicating that NRG-1β could reduce ROS production. PDH activity, CS activity, and ATP production were significantly higher in MI+NRG-1 group than in MI group (all P<0.05). qRT-PCR demonstrated an upregulated Glut-4, HK2 and CS, but downregulated PDK4 mRNA expression in MI+NRG-1 group compared with MI group (all P<0.01). Western blot assay showed significantly higher protein expression of NRG-1, p-ErbB4, Glut-4, HK2, PDH, CS in MI+NRG-1 group than in MI group (all P<0.01). Conclusion: NRG-1 could improve glucose uptake and utilization in myocardium by activating phosphorylation of myocardial ErbB4 receptor in MI rats, thus providing a therapeutic option for improving energy metabolism after MI.

DOI: https://doi.org/10.3760/cma.j.cn112148-20210628-00549
Clin Exp Pharmacol Physiol. 2021 Sep 14.

GLP-1 receptor agonist treatment of high-carbohydrate intake-induced metabolic syndrome provides pleiotropic effects on cardiac dysfunction through alleviations in electrical and intracellular Ca2+ abnormalities and mitochondrial dysfunction.

Aysegul Durak, Erman Akkus, Asena Gokcay Canpolat, Erkan Tuncay, Demet Corapcioglu, Belma Turan.

  The pleiotropic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the heart have been recognized in obese or diabetic patients. However, little is known regarding the molecular mechanisms of these agonists in cardioprotective actions under metabolic disturbances. We evaluated the effects of GLP-1R agonist liraglutide-treatment on left ventricular cardiomyocytes from high-carbohydrate induced metabolic syndrome rats (MetS-rats), characterized with insulin-resistance and cardiac dysfunction with a long-QT. Liraglutide (0.3 mg/kg for 4 weeks)-treatment of MetS-rats significantly reversed long-QT, through a shortening the prolonged action potential duration and recovering inhibited K+ -currents. We also determined a significant recovery in the leaky sarcoplasmic reticulum (SR) and high cytosolic Ca2+ -level, which are confirmed with a full recovery in activated Na+ /Ca2+ -exchanger currents (INCX ). Moreover, the liraglutide-treatment significantly reversed the depolarized mitochondrial membrane potential (MMP), increased production of oxidant markers, and cellular acidification together with the depressed ATP production. Our light microscopy analysis of isolated cardiomyocytes showed marked recoveries in the liraglutide-treated MetS-group such as marked reverses in highly dilated T-tubules and SR-mitochondria junctions. Moreover, we determined a significant increase in depressed GLUT4 protein level in liraglutide-treated MetS-group, possibly associated with recovery in casein kinase 2α. Overall, the study demonstrated a molecular mechanism of liraglutide-induced cardioprotection in MetS-rats, at most, via its pleiotropic effects, such as alleviation in the electrical abnormalities, Ca2+ -homeostasis, and mitochondrial-dysfunction in ventricular cardiomyocytes.

Keywords:  arrhythmia; electrical activity; insulin resistance; ion-homeostasis; sodium-calcium exchanger

DOI:  https://doi.org/10.1111/1440-1681.13590
Diabetes Metab Syndr Obes. 2021 ;14 3851-3863

Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats.

Qingmei Xu, Xin Tan, Wei Xian, Jiayi Geng, Haoyu Li, Bi Tang, Heng Zhang, Hongju Wang, Qin Gao, Pinfang Kang.

   Background: Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure.
Objective: This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage.
Materials and Methods: In our study, 30 Sprague-Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group).
Results: We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels.
Conclusion: In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.

Keywords:  cardiomyocyte; high glucose; inflammatory; irbesartan; necroptosis

DOI:  https://doi.org/10.2147/DMSO.S300388
Cardiovasc Drugs Ther. 2021 Sep 14.

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure.

Michele Correale, Pietro Mazzeo, Adriana Mallardi, Alessandra Leopizzi, Lucia Tricarico, Martino Fortunato, Michele Magnesa, Salvatore Tucci, Pasquale Maiellaro, Giuseppe Pastore, Olga Lamacchia, Massimo Iacoviello, Matteo Di Biase, Natale Daniele Brunetti.

   PURPOSE: The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study.
METHODS: Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up.
RESULTS: Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001).
CONCLUSIONS: Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.

Keywords:  Chronic heart failure; Endothelial dysfunction; Flow-mediated dilation; Gliflozins; SGLT2; Sodium-glucose-cotransporter-2 inhibitors; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1007/s10557-021-07254-3
Proteomics Clin Appl. 2021 Sep 12. e2100019

Phosphoproteomics analysis of diabetic cardiomyopathy in aging-accelerated mice and effects of D-Pinitol.

Xiao-Li Li, Fei Yu, Chun-Li Fu, Xin Yu, Mei Xu, Mei Cheng.

   PURPOSE: The molecular mechanisms of diabetic cardiomyopathy (DCM) development and D-pinitol in its treatment remain unclear. The present study is to explore the underlying mechanism of DCM in an elderly diabetic mouse model and to seek the protective targets of D-pinitol by phosphoproteomics.
EXPERIMENTAL DESIGN: We used streptozotocin to induce diabetes in SAMP 8 and D-pinitol (150 mg/kg/day) intragastrically administrated to diabetic mice for 8 weeks. The heart tissues were harvested for label-free phospho-proteomic analysis from diabetic mice. Some differentially regulated phosphorylation sites were confirmed by parallel reaction monitoring.
RESULTS: Our results showed that 612 phosphorylation sites on 454 proteins had their phosphorylation levels significantly changed in the heart of untreated diabetic mice (DM). Of these phosphorylation sites, 216 phosphorylation sites on 182 proteins were normalized after D-pinitol treatment. We analyzed the functional signaling pathways in the heart of D-pinitol treated diabetic mice (DMT), including glucagon signaling pathway, insulin signaling pathway, mitophagy, apoptosis, and longevity regulating pathway. Two consensus motifs identified were targeted by Src and epidermal growth factor receptor between DMT and DM groups.
CONCLUSIONS AND CLINICAL RELEVANCE: Our study might help to better understand the mechanism of DCM, provide novel targets for estimating the protective effects of D-pinitol. This article is protected by copyright. All rights reserved.

Keywords:  aging; cardiac fibrosis, diabetic cardiomyopathy, D-pinitol, phosphoproteomics

DOI:  https://doi.org/10.1002/prca.202100019