bims-hafaim 2021-06-20 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–06–20
seven papers selected by
Kyle McCommis, Saint Louis University

Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodeling and heart failure.
Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.
Peroxiredomin-4 ameliorates lipotoxicity-induced oxidative stress and apoptosis in diabetic cardiomyopathy.
MicroRNA-17-5p Promotes Cardiac Hypertrophy by Targeting Mfn2 to Inhibit Autophagy.
PPAR control of metabolism and cardiovascular functions.
Comparison of cardiovascular outcomes and cardiometabolic risk factors between patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors: a meta-analysis.
Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway.

Cardiovasc Res. 2021 Jun 16. pii: cvab206. [Epub ahead of print]

Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodeling and heart failure.

Michael R Jackson, Kristie D Cox, Simon D P Baugh, Luke Wakeen, Adel A Rashad, Patrick Y S Lam, Boris Polyak, Marilyn Schuman Jorns.

   AIMS: Hydrogen sulfide (H2S) is a potent signaling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide: quinone oxidoreductase (SQOR) catalyzes the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signaling. Our aim here was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF.
METHODS AND RESULTS: We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy.
CONCLUSION: We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.
TRANSLATIONAL PERSPECTIVE: In HFrEF there is a compelling need for new drugs that mitigate the pathological remodeling induced by injury and improve patient survival. This study identifies SQOR-inhibiting drugs as a promising first-in-class therapy for HFrEF patients. Due to the well-established protective properties of H2S-induced signaling in renal physiology and disease, this novel class of heart failure therapeutics may also address the large unmet need of therapies for approximately 50% of heart failure patients that have coexisting chronic renal dysfunction.

Keywords:  Cardiac disease; Cardioprotection; Heart failure; Hydrogen sulfide signaling; Sulfide: quinone oxidoreductase

DOI:  https://doi.org/10.1093/cvr/cvab206
Circ Heart Fail. 2021 Jun;14(6): e008289

Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.

Siting Zhu, Ze'e Chen, Mason Zhu, Ying Shen, Leonardo J Leon, Liguo Chi, Simone Spinozzi, Changming Tan, Yusu Gu, Anh Nguyen, Yi Zhou, Wei Feng, Frédéric M Vaz, Xiaohong Wang, Asa B Gustafsson, Sylvia M Evans, Ouyang Kunfu, Xi Fang.

   BACKGROUND: Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking.
METHODS: We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).
RESULTS: Taz cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity.
CONCLUSIONS: Our mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.

Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mice; mitochondria

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.121.008289
Biomed Pharmacother. 2021 Jun 12. pii: S0753-3322(21)00562-X. [Epub ahead of print]141 111780

Peroxiredomin-4 ameliorates lipotoxicity-induced oxidative stress and apoptosis in diabetic cardiomyopathy.

Bin Zhang, Xiaoya Li, Guoxin Liu, Chenyang Zhang, Xuelian Zhang, Qiang Shen, Guibo Sun, Xiaobo Sun.

  Diabetic cardiomyopathy (DCM), one severe complication in the diabetes, leads to high mortality in the diabetic patients. However, the understanding of molecular mechanisms underlying DCM is far from completion. Herein, we investigated the disease-related differences in the proteomes of DCM based on db/db mice and verified the protective roles of peroxiredoxin-4 (Prdx4) in H9c2 cardiomyocytes treated by palmitic acid (PA). Fasting blood glucose (FBG) and cardiac function was detected in the 6-month-old control and diabetic mice. The hearts were then collected and analyzed by a coupled label-free and mass spectrometry approach. In vivo investigation indicated that body weight and FBG of db/db mice markedly increased, and diabetic heart exhibited obvious cardiac hypertrophy and lipid droplet accumulation, and cardiac dysfunction as is indicated by the increases of left ventricle posterior wall thickness in systole (LVPWd) and diastole (LVPWs), and reduction of fractional shortening (FS). We used proteomic analysis and then detected a grand total of 2636 proteins. 175 differentially expressed proteins (DEPs) were markedly detected in the diabetic heart. Thereinto, Prdx4 was markedly down-regulated in the diabetic heart. In vitro experiments revealed that 250 μM PA significantly inhibited viability of H9c2 cell. PA induced much accumulation of lipid droplet in cardiomyocytes and resulted in an increase of mRNA expressions of lipogenic genes (FASN and SCD1) and cardiac hypertrophic genes. Additionally, protein level of Prdx4 evidently reduced in the PA-treated H9c2 cell. It was further found that shRNA-mediated Prdx4 knockdown exacerbated PA-induced oxidative stress and cardiomyocyte apoptosis, whereas overexpressing Prdx4 in the H9c2 cells noteworthily limited PA-induced ROS generation and cardiomyocytes apoptosis. These data collectively reveal the essential role of abnormal Prdx4 in pathological alteration of DCM, and provide potentially therapeutic target for the prevention of DCM.

Keywords:  Diabetes mellitus; Diabetic cardiomyopathy; Peroxiredoxin-4; Proteomes

DOI:  https://doi.org/10.1016/j.biopha.2021.111780
Cardiovasc Toxicol. 2021 Jun 12.

MicroRNA-17-5p Promotes Cardiac Hypertrophy by Targeting Mfn2 to Inhibit Autophagy.

Xuan Xu, Yi-Ling Su, Jia-Yu Shi, Qi Lu, Chu Chen.

  Pathological cardiac hypertrophy is the leading cause of heart failure, and miRNAs have been recognized as key factors in cardiac hypertrophy. This study aimed to elucidate whether miR-17-5p affects cardiac hypertrophy by targeting the mitochondrial fusion protein mitofusin 2 (Mfn2)-mediated phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and regulating autophagy. miR-17-5p expression was shown to be upregulated both in vivo and in vitro. In addition, a miR-17-5p inhibitor significantly reversed AngII-induced cell hypertrophy in neonatal rat left ventricle myocytes (NRVMs). In contrast to miR-17-5p expression, Mfn2 expression was inhibited in rat hearts at 4 weeks after transverse aortic constriction (TAC) and in an Ang II-induced cell hypertrophy model. We examined miR-17-5p targeting of Mfn2 by dual luciferase reporter and Western blot assays. In addition, we also verified the relationship between Mfn2 and the PI3K/AKT/mTOR pathway. Mfn2 overexpression attenuated miR-17-5p-induced cell hypertrophy, and in rat myocardial tissue, miR-17-5p induced autophagy inhibition. In summary, the results of the present study demonstrated that miR-17-5p inhibits Mfn2 expression, activates the PI3K/AKT/mTOR pathway and suppresses autophagy to promote cardiac hypertrophy.

Keywords:  Autophagy; Cardiac hypertrophy; Mfn2; MicroRNA-17-5p; PI3K/AKT/mTOR pathway

DOI:  https://doi.org/10.1007/s12012-021-09667-w
Nat Rev Cardiol. 2021 Jun 14.

PPAR control of metabolism and cardiovascular functions.

David Montaigne, Laura Butruille, Bart Staels.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.

DOI: https://doi.org/10.1038/s41569-021-00569-6
Eur J Prev Cardiol. 2021 Jun 17. pii: zwab099. [Epub ahead of print]

Comparison of cardiovascular outcomes and cardiometabolic risk factors between patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors: a meta-analysis.

Siwen Wang, Ting Wu, Zhihong Zuo, Ping Jin, Xuan Luo, Meichun Deng.

   AIMS : Prevention of cardiovascular outcomes is a goal of the management of patients with type 2 diabetes mellitus patients as important as lowering blood glucose levels. Among the various glucose-lowering agents, the effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2Is) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) on cardiovascular outcomes have become the focus of recent researches.
METHODS AND RESULTS : A systematic search was performed through several online database. All studies that compared the effects of SGLT-2Is and DPP-4Is on cardiovascular outcomes and cardiometabolic risk factors were reviewed. A total of 30 studies were included. Compared with DPP-4Is, SGLT-2Is treatment reduced the risk of stroke [risk ratio (RR) = 0.80; 95% confidence interval (CI), 0.76-0.84], myocardial infarction (RR = 0.85; 95% CI, 0.81-0.89), heart failure (RR = 0.58; 95% CI, 0.54-0.62), cardiovascular mortality (RR = 0.55; 95% CI, 0.51-0.60), and all-cause mortality (RR = 0.60; 95% CI, 0.57-0.63). In addition, SGLT-2Is presented favourable effects on hemoglobinA1c, fasting plasma glucose, systolic blood pressure, and diastolic blood pressure. The differences in blood lipids were also compared.
CONCLUSION: Sodium-glucose cotransporter-2 inhibitors are superior to DPP-4Is in terms of cardiovascular outcomes. Sodium-glucose cotransporter-2 inhibitors bring more benefits with respect to the cardiometabolic risk factors.

Keywords:  Cardiovascular outcomes •Type 2 diabetes; DPP-4 inhibitors; SGLT-2 inhibitors

DOI:  https://doi.org/10.1093/eurjpc/zwab099
iScience. 2021 Jun 25. 24(6): 102521

Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway.

Pengbo Sun, Yangyang Wang, Yipei Ding, Jingyi Luo, Jin Zhong, Naihan Xu, Yaou Zhang, Weidong Xie.

  Lipotoxicity plays an important role in the development of diabetic heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significantly beneficial effects on HF. In this study, we evaluated the protective effects and mechanism of CAN in the hearts of C57BL/6J mice induced by high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and in HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro. The results showed that CAN significantly ameliorated heart functions and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. Furthermore, CAN seemed to bind to the mammalian target of rapamycin (mTOR) and then inhibit mTOR phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression. These results indicated that CAN might attenuate lipotoxicity in cardiomyocytes by inhibiting the mTOR/HIF-1α pathway and then show protective effects on diabetic hearts.

Keywords:  Human metabolism; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2021.102521