Knockdown of SCN5A alters metabolic-associated genes and aggravates hypertrophy in the cardiomyoblast.

SCN5A mutations have been reported to cause various cardiomyopathies in humans. Most of the SCN5A mutations causes loss of function and thereby, alters the overall cellular function. Therefore, to understand the loss of SCN5A function in cardiomyocytes, we have knocked down the SCN5A gene (SCN5A-KD) in H9c2 cells and explored the cell phenotype and molecular behaviors in the presence and absence of isoproterenol (ISO), an adrenergic receptor agonist that induces cardiac hypertrophy. Expression of several genes related to hypertrophy, inflammation, fibrosis, and energy metabolism pathways were evaluated. It was found that the mRNA expression of hypertrophy-related gene, brain (B-type) natriuretic peptide (BNP) was significantly increased in SCN5A-KD cells as compared to 'control' H9c2 cells. There was a further increase in the mRNA expressions of BNP and ßMHC in SCN5A-KD cells after ISO treatment compared to their respective controls. Pro-inflammatory cytokine, tumor necrosis factor-alpha expression was significantly increased in 'SCN5A-KD' H9c2 cells. Further, metabolism-related genes like glucose transporter type 4, cluster of differentiation 36, peroxisome proliferator-activated receptor alpha, and peroxisome proliferator-activated receptor-gamma were significantly elevated in the SCN5A-KD cells as compared to the control cells. Upregulation of these metabolic genes is associated with increased ATP production. The study revealed that SCN5A knock-down causes alteration of gene expression related to cardiac hypertrophy, inflammation, and energy metabolism pathways, which may promote cardiac remodelling and cardiomyopathy.

Role of Biomaterials in Cardiac Repair and Regeneration: Therapeutic Intervention for Myocardial Infarction.

Heart failure or myocardial infarction (MI) is one of the world's leading causes of death. Post MI, the heart can develop pathological conditions such as ischemia, inflammation, fibrosis, and left ventricular dysfunction. However, current surgical approaches are sufficient for enhancing myocardial perfusion but are unable to reverse the pathological changes. Tissue engineering and regenerative medicine approaches have shown promising effects in the repair and replacement of injured cardiomyocytes. Additionally, biomaterial scaffolds with or without stem cells are established to provide an effective environment for cardiac regeneration. Excipients loaded with growth factors, cytokines, oligonucleotides, and exosomes are found to help in such cardiac eventualities by promoting angiogenesis, cardiomyocyte proliferation, and reducing fibrosis, inflammation, and apoptosis. Injectable hydrogels, nanocarriers, cardiac patches, and vascular grafts are some excipients that can help the self-renewal in the damaged heart but are not understood well yet, in the context of used biomaterials. This review focuses on the use of various biomaterial-based approaches for the regeneration and repair of cardiac tissue postoccurrence of MI. It also discusses the outlines of cardiac remodeling and current therapeutic approaches after myocardial infarction, which are translationally important with respect to used biomaterials. It provides comprehensive details of the biomaterial-based regenerative approaches, which are currently the focus of the research for cardiac repair and regeneration and can provide a broad outline for further improvements.

Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure.

Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and ß. The role of GSK-3α and GSK-3ß in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3ß is downregulated in hypertrophy and heart failure and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3ß leads to endogenous cardiomyocyte proliferation and cardiac regeneration via the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac-specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3ß KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off-target effects. This review focuses on the isoform-specific functions of GSK-3 that will help in better understanding the role of GSK-3α and GSK-3ß in cardiac biology and pave the way for the development of new isoform-specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

Allylmethylsulfide, a Sulfur Compound Derived from Garlic, Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats.

Allylmethylsulfide (AMS) is a novel sulfur metabolite found in the garlic-fed serum of humans and animals. In the present study, we have observed that AMS is safe on chronic administration and has a potential antihypertrophic effect. Chronic administration of AMS for 30 days did not cause any significant differences in the body weight, electrocardiogram, food intake, serum biochemical parameters, and histopathology of vital organs. Single-dose pharmacokinetics of AMS suggests that AMS is rapidly metabolized into Allylmethylsulfoxide (AMSO) and Allylmethylsulfone (AMSO2). To evaluate the efficacy of AMS, cardiac hypertrophy was induced by subcutaneous implantation of ALZET® osmotic minipump containing isoproterenol (~5 mg/kg/day), cotreated with AMS (25 and 50 mg/kg/day) and enalapril (10 mg/kg/day) for 2 weeks. AMS and enalapril significantly reduced cardiac hypertrophy as studied by the heart weight to body weight ratio and mRNA expression of fetal genes (ANP and ß-MHC). We have observed that TBARS, a parameter of lipid peroxidation, was reduced and the antioxidant enzymes (glutathione, catalase, and superoxide dismutase) were improved in the AMS and enalapril-cotreated hypertrophic hearts. The extracellular matrix (ECM) components such as matrix metalloproteinases (MMP2 and MMP9) were significantly upregulated in the diseased hearts; however, with the AMS and enalapril, it was preserved. Similarly, caspases 3, 7, and 9 were upregulated in hypertrophic hearts, and with the AMS and enalapril treatment, they were reduced. Further to corroborate this finding with in vitro data, we have checked the nuclear expression of caspase 3/7 in the H9c2 cells treated with isoproterenol and observed that AMS cotreatment reduced it significantly. Histopathological investigation of myocardium suggests AMS and enalapril treatment reduced fibrosis in hypertrophied hearts. Based on our experimental results, we conclude that AMS, an active metabolite of garlic, could reduce isoproterenol-induced cardiac hypertrophy by reducing oxidative stress, apoptosis, and stabilizing ECM components.