bims-hafaim 2021-10-17 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–10–17
six papers selected by
Kyle McCommis, Saint Louis University

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes.
The role of hyperglycaemia in the development of diabetic cardiomyopathy.
Dapagliflozin Mediates Plin5/PPARα Signaling Axis to Attenuate Cardiac Hypertrophy.
The cardioprotective effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in rats with isoproterenol-induced cardiomyopathy.
Heart failure in diabetes.
Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction.

Front Cardiovasc Med. 2021 ;8 748156

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes.

Ran Xu, Le Kang, Siang Wei, Chunjie Yang, Yuanfeng Fu, Zhiwen Ding, Yunzeng Zou.

  Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

Keywords:  Pink1; Samm50; cardiac hypertrophy; heart failure; mitophagy

DOI:  https://doi.org/10.3389/fcvm.2021.748156
Arch Cardiovasc Dis. 2021 Oct 06. pii: S1875-2136(21)00147-9. [Epub ahead of print]

The role of hyperglycaemia in the development of diabetic cardiomyopathy.

Magali Samia El Hayek, Laura Ernande, Jean-Pierre Benitah, Ana-Maria Gomez, Laetitia Pereira.

  Diabetes mellitus is a metabolic disorder with a chronic hyperglycaemic state. Cardiovascular diseases are the primary cause of mortality in patients with diabetes. Increasing evidence supports the existence of diabetic cardiomyopathy, a cardiac dysfunction with impaired cardiac contraction and relaxation, independent of coronary and/or valvular complications. Diabetic cardiomyopathy can lead to heart failure. Several preclinical and clinical studies have aimed to decipher the underlying mechanisms of diabetic cardiomyopathy. Among all the co-factors, hyperglycaemia seems to play an important role in this pathology. Hyperglycaemia has been shown to alter cardiac metabolism and function through several deleterious mechanisms, such as oxidative stress, inflammation, accumulation of advanced glycated end-products and upregulation of the hexosamine biosynthesis pathway. These mechanisms are responsible for the activation of hypertrophic pathways, epigenetic modifications, mitochondrial dysfunction, cell apoptosis, fibrosis and calcium mishandling, leading to cardiac stiffness, as well as contractile and relaxation dysfunction. This review aims to describe the hyperglycaemic-induced alterations that participate in diabetic cardiomyopathy, and their correlation with the severity of the disease and patient mortality, and to provide an overview of cardiac outcomes of glucose-lowering therapy.

Keywords:  Cardiomyopathie; Cardiomyopathy; Diabetes; Diabète; Glucose

DOI:  https://doi.org/10.1016/j.acvd.2021.08.004
Front Pharmacol. 2021 ;12 730623

Dapagliflozin Mediates Plin5/PPARα Signaling Axis to Attenuate Cardiac Hypertrophy.

Jing Yu, Huanhuan Zhao, Xin Qi, Liping Wei, Zihao Li, Chunpeng Li, Xiaoying Zhang, Hao Wu.

  Objective: The purpose of this study was to investigate the effect of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, on relieving cardiac hypertrophy and its potential molecular mechanism. Methods: Cardiac hypertrophy induced by abdominal aortic constriction (AAC) in mice, dapagliflozin were administered in the drinking water at a dose of 25 mg/kg/d for 12 weeks was observed. Echocardiography was used to detect the changes of cardiac function, including LVEF, LVFS, LVEDd, LVEDs, HR and LV mass. Histological morphological changes were evaluated by Masson trichrome staining and wheat germ agglutinin (WGA) staining. The enrichment of differential genes and signal pathways after treatment was analyzed by gene microarray cardiomyocyte hypertrophy was induced by AngII (2 μM) and the protective effect of dapagliflozin (1 μM) was observed in vitro. The morphological changes of myocardial cells were detected by cTnI immunofluorescence staining. ELISA and qRT-PCR assays were performed to detect the expressions levels of cardiac hypertrophy related molecules. Results: After 12 weeks of treatment, DAPA significantly ameliorated cardiac function and inhibited cardiac hypertrophy in AAC-induced mice. In vitro, DAPA significantly inhibited abnormal hypertrophy in AngII-induced cardiacmyocytes. Both in vivo and in vitro experiments have confirmed that DAPA could mediate the Plin5/PPARα signaling axis to play a protective role in inhibiting cardiac hypertrophy. Conclusion: Dapagliflozin activated the Plin5/PPARα signaling axis and exerts a protective effect against cardiac hypertrophy.

Keywords:  AngII; Plin5/PPARα signaling; cardiac hypertrophy; dapagliflozin; mice

DOI:  https://doi.org/10.3389/fphar.2021.730623
Am J Transl Res. 2021 ;13(9): 10950-10961

The cardioprotective effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in rats with isoproterenol-induced cardiomyopathy.

Fang-Zheng Wang, Wen-Bo Wei, Xin Li, Jun-Yu Huo, Wan-Ying Jiang, Hong-Yu Wang, Pei Qian, Zhen-Zhen Li, Ye-Bo Zhou.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) has been reported to improve glycemic control. This study was designed to investigate the effects of SGLT2i dapagliflozin (dapa) on cardiomyopathy induced by isoproterenol (ISO) and its potential mechanisms. Fifty male Sprague Dawley rats were randomly assigned to the control (n=10) and the ISO (2.5 mg/kg/day)-treated groups (n=40). After 2 weeks, the 28 surviving rats with obvious left ventricular dysfunction in the ISO group were randomized into three medication groups, including the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan group (S/V, n=9), the dapa group (n=9), and the ISO group (n=10) for 4 weeks. Next, electrical programmed stimulation was performed in all the groups to evaluate their susceptibility to ventricular arrhythmias (VAs). Compared to the ISO rats, the dapa administration not only effectively reduced the cumulative risk of death, the myocardial fibrosis, the plasma angiotensin II levels and its functional receptor AT1R protein expressions in the heart, and the proinflammatory cytokine levels in the cardiac tissue of the ISO-treated rats, but it also improved their cardiac function and inhibited oxidative stress. These effects were similar to S/V. However, dapa showed a greater efficacy than S/V in reducing the left ventricular end-diastolic volumes, lowing the heart rates and VAs, and decreasing the body weights and plasma glucose levels. The mechanisms by which dapa exerts protective effects on cardiomyopathy may be related to its indirect antioxidant capacity and direct hypoglycemic action.

Keywords: Sodium-glucose cotransporter 2 inhibitors; cardiac function; fibrosis; inflammation; oxidative stress; ventricular arrhythmias
Metabolism. 2021 Oct 07. pii: S0026-0495(21)00210-9. [Epub ahead of print] 154910

Heart failure in diabetes.

Stanislovas S Jankauskas, Urna Kansakar, Fahimeh Varzideh, Scott Wilson, Pasquale Mone, Angela Lombardi, Jessica Gambardella, Gaetano Santulli.

  Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present an overview of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.

Keywords:  ATP; CaMKII; Calcium; Diabetes mellitus; Endothelium; FOXO1; GLUT4; Glucose; HFpEF; Heart Failure; Mitochondria; NADH; NOX; PPARα; PPARγ; ROS; RYR; SERCA; T1DM; T2DM; UCP3; VSMC; adrenergic receptors; bioenergetics; cardiomyocytes; cardiovascular endocrinology; diabetic cardiomyopathy; diastolic dysfunction; fibroblasts; fibrosis; free fatty acids; glycerolipid biosynthetic pathway; hexosamine biosynthetic pathway; mTOR; nitric oxide; oxidative stress; pentose phosphate pathway; phospholamban; pyruvate; substrate switch

DOI:  https://doi.org/10.1016/j.metabol.2021.154910
Am J Cardiovasc Drugs. 2021 Oct 15.

Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction.

Hannah A Blair.

Dapagliflozin [Farxiga® (USA); Forxiga® (EU)], a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was recently approved in the USA and the EU for the treatment of adults with symptomatic heart failure with reduced ejection fraction (HFrEF). The cardiovascular (CV) benefits of dapagliflozin were first observed in the DECLARE-TIMI 58 trial, in which dapagliflozin 10 mg/day significantly reduced the risk of CV death or hospitalization for HF in patients with type 2 diabetes mellitus (T2DM) who had or were at risk for atherosclerotic CV disease. In the subsequent DAPA-HF trial, dapagliflozin 10 mg/day in addition to standard of care was associated with a significantly lower risk of worsening HF or CV death than placebo in patients with HFrEF, regardless of the presence or absence of T2DM. The benefits of dapagliflozin also remained consistent regardless of background HF therapies. Dapagliflozin was generally well tolerated, with an overall safety profile consistent with its known safety profile in other indications. In conclusion, dapagliflozin is an effective and generally well-tolerated treatment that represents a valuable new addition to the options available for symptomatic HFrEF.

DOI: https://doi.org/10.1007/s40256-021-00503-8