bims-hafaim 2021-09-26 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–09–26
ten papers selected by
Kyle McCommis, Saint Louis University

TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway.
Structural and functional alterations in heart and skeletal muscle following severe TAC in mice: impact of moderate exercise training.
Effect of Sacubitril/Valsartan Combined with Dapagliflozin on Long-Term Cardiac Mortality in Heart Failure with Reduced Ejection Fraction.
Ubiquitin Ligase Wwp1 Gene Deletion Attenuates Diastolic Dysfunction in Pressure Overload Hypertrophy.
Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT1 receptors.
Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation.
Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy.
Insulin signaling alters antioxidant capacity in the diabetic heart.
Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.
Metabolic Processes are Potential Biological Processes Distinguishing Nonischemic Dilated Cardiomyopathy from Ischemic Cardiomyopathy: A Clue from Serum Proteomics.

Front Cardiovasc Med. 2021 ;8 687540

TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway.

Yanan Pang, Minglu Ma, Dong Wang, Xun Li, Li Jiang.

  Background: TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown. Methods and Results: In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4-8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, in vitro experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice. Conclusions: Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.

Keywords:  AKT signal pathway; TRAF family member associated NF-κB activator; pathological cardiac hypertrophy; scaffold protein; tansgenic mice

DOI:  https://doi.org/10.3389/fcvm.2021.687540
Biol Res. 2021 Sep 19. 54(1): 31

Structural and functional alterations in heart and skeletal muscle following severe TAC in mice: impact of moderate exercise training.

Julia Böttner, Sarah Werner, Volker Adams, Sarah Knauth, Angela Kricke, Holger Thiele, Petra Büttner.

   BACKGROUND: Heart failure (HF) is the leading cause of death in western countries. Cardiac dysfunction is accompanied by skeletal alterations resulting in muscle weakness and fatigue. Exercise is an accepted interventional approach correcting cardiac and skeletal dysfunction, thereby improving mortality, re-hospitalization and quality of life. Animal models are used to characterize underpinning mechanisms. Transverse aortic constriction (TAC) results in cardiac pressure overload and finally HF. Whether exercise training improves cardiac remodeling and peripheral cachexia in the TAC mouse model was not analyzed yet. In this study, 2 weeks post TAC animals were randomized into two groups either performing a moderate exercise program (five times per week at 60% VO2 max for 40 min for a total of 8 weeks) or staying sedentary.
RESULTS: In both TAC groups HF characteristics reduced ejection fraction (- 15% compared to sham, p < 0.001), cardiac remodeling (+ 22.5% cardiomyocyte cross sectional area compared to sham; p < 0.001) and coronary artery congestion (+ 34% diameter compared to sham; p = 0.008) were observed. Unexpectedly, peripheral cachexia was not detected. Furthermore, compared to sedentary group animals from the exercise group showed aggravated HF symptoms [heart area + 9% (p = 0.026), heart circumference + 7% (p = 0.002), right ventricular wall thickness - 30% (p = 0.003)] while muscle parameters were unchanged [Musculus soleus fiber diameter (p = 0.55), Musculus extensor digitorum longus contraction force (p = 0.90)].
CONCLUSION: The severe TAC model is inappropriate to study moderate exercise effects in HF with respect to cardiac and skeletal muscle improvements. Further, the phenotype induced by different TAC procedures should be well documented and taken into account when planning experiments.

Keywords:  Force production; Heart failure; Intervention; Moderate exercise; Peripheral cachexia; Transverse aortic constriction; Treadmill

DOI:  https://doi.org/10.1186/s40659-021-00354-2
Angiology. 2021 Sep 24. 33197211047329

Effect of Sacubitril/Valsartan Combined with Dapagliflozin on Long-Term Cardiac Mortality in Heart Failure with Reduced Ejection Fraction.

Umut Karabulut, Kudret Keskin, Dilay Karabulut, Ece Yiğit, Zerrin Yiğit.

  The angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan and sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin have been shown to reduce rehospitalization and cardiac mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We aimed to compare the long-term cardiac and all-cause mortality of ARNI and dapagliflozin combination therapy against ARNI monotherapy in patients with HFrEF. This retrospective study involved 244 patients with HF with New York Heart Association (NYHA) class II-IV symptoms and ejection fraction ≤40%. The patients were divided into 2 groups: ARNI monotherapy and ARNI+dapagliflozin. Median follow-up was 2.5 (.16-3.72) years. One hundred and seventy-five (71.7%) patients were male, and the mean age was 65.9 (SD, 10.2) years. Long-term cardiac mortality rates were significantly lower in the ARNI+dapagliflozin group (7.4%) than in the ARNI monotherapy group (19.5%) (P = .01). Dapagliflozin [Hazard Ratio (HR) [95% Confidence Interval (CI)] = .29 [.10-.77]; P = .014] and left ventricular ejection fraction (LVEF) [HR (95% CI) = .89 (.85-.93); P < .001] were found to be independent predictors of cardiac mortality. Our study showed a significant reduction in cardiac mortality with ARNI and dapagliflozin combination therapy compared with ARNI monotherapy.

Keywords:  combination therapy; dapagliflozin; heart failure; mortality; sacubitril; valsartan

DOI:  https://doi.org/10.1177/00033197211047329
Am J Physiol Heart Circ Physiol. 2021 Sep 24.

Ubiquitin Ligase Wwp1 Gene Deletion Attenuates Diastolic Dysfunction in Pressure Overload Hypertrophy.

Laura B Snyder, Yimu Lai, Heather Doviak, Lisa A Freeburg, Valerie K Laney, Amber Moore, Kia N Zellars, Lydia E Matesic, Francis G Spinale.

   BACKGROUND: Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and accompanied by abnormal extracellular matrix (ECM) accumulation. The E3 ubiquitin ligase WWP1 is a fundamental determinant ECM turnover. We tested the hypothesis that genetic ablation of Wwp1 would alter the progression of LVPO induced HFpEF.
METHODS/RESULTS: LV echocardiography in mice with global Wwp1 deletion (n=41; Wwp1-/-) was performed at 12 weeks of age (Baseline) and then at 2 and 4 weeks following LVPO (transverse aortic banding) or surgery without LVPO induction. Age-matched wild type mice (Wwp1+/+; n=33) underwent identical protocols. LV EF remained constant and unchanged with LVPO and LV mass increased in both groups but was lower in the Wwp1-/- mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 + 0.46 in Wwp1+/+ but was 1.73 + 0.19 in the Wwp1-/- group (p<0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in Wwp1-/- compared to the Wwp1+/+ group at 4 weeks post-LVPO (p<0.05) and was paralleled by a similar difference in LV fibrillar collagen content as measured by histochemistry. Moreover, mRNA levels for determinants favoring ECM accumulation, such as transforming growth factor (TGF) increased with LVPO, but were lower in the Wwp1-/- group.
SUMMARY: The absence of Wwp1 reduced the development of LVH and subsequent progression to HFpEF. Modulating the WWP1 pathway could be a therapeutic target to alter the natural history of HFpEF.

Keywords:  cardiac hypertrophy; diastolic dysfunction; heart failure; ubiquitin ligase WWP1; ventricular remodeling

DOI:  https://doi.org/10.1152/ajpheart.00032.2021
J Mol Cell Cardiol. 2021 Sep 20. pii: S0022-2828(21)00178-4. [Epub ahead of print]

Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT1 receptors.

Li Lin, Ning Zhou, Le Kang, Qi Wang, Jian Wu, Xiaoyan Wang, Chunjie Yang, Guoping Zhang, Yunqin Chen, Hong Jiang, Ruizhen Chen, Xiangdong Yang, Aijun Sun, Hui Gong, Jun Ren, Hiroshi Akazawa, Komuro Issei, Junbo Ge, Cheng Yang, Yunzeng Zou.

  It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT1-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT1-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.

Keywords:  AT(1) receptor; Angiotensin II; Cardiomyocyte hypertrophy; LOX-1; Ox-LDL

DOI:  https://doi.org/10.1016/j.yjmcc.2021.09.006
Hum Mol Genet. 2021 Sep 22. pii: ddab216. [Epub ahead of print]

Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation.

César Vásquez-Trincado, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeová, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert.

Friedreich's ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron-sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood, though are expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

DOI: https://doi.org/10.1093/hmg/ddab216
Front Physiol. 2021 ;12 672252

Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy.

Alex M Parker, Mitchel Tate, Darnel Prakoso, Minh Deo, Andrew M Willis, David M Nash, Daniel G Donner, Simon Crawford, Helen Kiriazis, Cesare Granata, Melinda T Coughlan, Miles J De Blasio, Rebecca H Ritchie.

  People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.

Keywords:  diabetes; diabetic cardiomyopathy; experimental – animal models; heart; mitochondria; mitochondrial function

DOI:  https://doi.org/10.3389/fphys.2021.672252
Redox Biol. 2021 Sep 20. pii: S2213-2317(21)00299-8. [Epub ahead of print]47 102140

Insulin signaling alters antioxidant capacity in the diabetic heart.

Satoshi Matsuzaki, Craig Eyster, Maria F Newhardt, Jennifer R Giorgione, Caroline Kinter, Zachary T Young, Michael Kinter, Kenneth M Humphries.

  Diabetic cardiomyopathy is associated with an increase in oxidative stress. However, antioxidant therapy has shown a limited capacity to mitigate disease pathology. The molecular mechanisms responsible for the modulation of reactive oxygen species (ROS) production and clearance must be better defined. The objective of this study was to determine how insulin affects superoxide radical (O2•-) levels. O2•- production was evaluated in adult cardiomyocytes isolated from control and Akita (type 1 diabetic) mice by spin-trapping electron paramagnetic resonance spectroscopy. We found that the basal rates of O2•- production were comparable in control and Akita cardiomyocytes. However, culturing cardiomyocytes without insulin resulted in a significant increase in O2•- production only in the Akita group. In contrast, O2•- production was unaffected by high glucose and/or fatty acid supplementation. The increase in O2•- was due in part to a decrease in superoxide dismutase (SOD) activity. The PI3K inhibitor, LY294002, decreased Akita SOD activity when insulin was present, indicating that the modulation of antioxidant activity is through insulin signaling. The effect of insulin on mitochondrial O2•- production was evaluated in Akita mice that underwent a 1-week treatment of insulin. Mitochondria isolated from insulin-treated Akita mice produced less O2•- than vehicle-treated diabetic mice. Quantitative proteomics was performed on whole heart homogenates to determine how insulin affects antioxidant protein expression. Of 29 antioxidant enzymes quantified, thioredoxin 1 was the only one that was significantly enhanced by insulin treatment. In vitro analysis of thioredoxin 1 revealed a previously undescribed capacity of the enzyme to directly scavenge O2•-. These findings demonstrate that insulin has a role in mitigating cardiac oxidative stress in diabetes via regulation of endogenous antioxidant activity.

Keywords:  Cardiomyocytes; Diabetes; EPR; Heart; Insulin; Thioredoxin

DOI:  https://doi.org/10.1016/j.redox.2021.102140
J Am Coll Cardiol. 2021 Sep 28. pii: S0735-1097(21)05787-9. [Epub ahead of print]78(13): 1337-1348

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

EMPEROR-Reduced Trial Committees and Investigators

   BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.
OBJECTIVES: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
METHODS: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP.
RESULTS: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension.
CONCLUSIONS: Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Keywords:  cardiovascular outcomes; empagliflozin; heart failure; kidney outcomes; systolic blood pressure

DOI:  https://doi.org/10.1016/j.jacc.2021.07.049
Pharmgenomics Pers Med. 2021 ;14 1169-1184

Metabolic Processes are Potential Biological Processes Distinguishing Nonischemic Dilated Cardiomyopathy from Ischemic Cardiomyopathy: A Clue from Serum Proteomics.

Guangyong Huang, Zhiqi Huang, Yunling Peng, Yuehai Wang, Weitao Liu, Yuzeng Xue, Wenbo Yang.

   Background: Ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (DCM) are the two most common causes of heart failure. However, our understanding of the specific proteins and biological processes distinguishing DCM from ICM remains insufficient.
Materials and Methods: The proteomics analyses were performed on serum samples from ICM (n=5), DCM (n=5), and control (n=5) groups. Proteomics and bioinformatics analyses, including weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA), were performed to identify the hub circulating proteins and the hub biological processes in ICM and DCM.
Results: The analysis of differentially expressed proteins and WGCNA identified the hub circulating proteins in ICM (GAPDH, CLSTN1, VH3, CP, and ST13) and DCM (one downregulated protein, FGG; 18 upregulated proteins, including HEL-S-276, IGK, ALDOB, HIST1H2BJ, HEL-S-125m, RPLP2, EL52, NCAM1, P4HB, HEL-S-99n, HIST1H4L, HIST2H3PS2, F8, ERP70, SORD, PSMA3, PSMB6, and PSMA6). The mRNA expression of the heart specimens from GDS651 validated that ALDOB, GAPDH, RPLP2, and IGK had good abilities to distinguish DCM from ICM. In addition, GSEA results showed that cell proliferation and differentiation were the hub biological processes related to ICM, while metabolic processes and cell signaling transduction were the hub biological processes associated with DCM.
Conclusion: The present study identified five dysregulated hub circulating proteins among ICM patients and 19 dysregulated hub circulating proteins among DCM patients. Cell proliferation and differentiation were significantly enriched in ICM. Metabolic processes were strongly enhanced in DCM and may be used to distinguish DCM from ICM.

Keywords:  dilated cardiomyopathy; gene set enrichment analysis; ischemic cardiomyopathy; proteomics; weighted gene co-expression network analysis

DOI:  https://doi.org/10.2147/PGPM.S323379