![]() Rac1 regulates hypertrophic remodeling of cardiomyocytes that is related to the MAPK cascade activation. Together with RhoA, Rac1 represents the most characterized member of small G proteins in myocardial signaling. In particular, RhoA plays a pivotal regulatory role in motility, proliferation, and differentiation of cardiomyocytes in response to stress conditions. In myocardial hypertrophy and heart failure, Rho and Rac are implicated in signalling pathways that regulate various cellular functions, such as actin stress fiber assembly and focal adhesions. G protein coupled receptor (GPCR) and tyrosine kinase receptor (RTK), by activating ERK1/2, could be involved in the mitigation of hypertrophic cardiomyopathy treatment. Therefore, the understanding of cell signaling events that regulate cardiac function can facilitate therapeutic approaches to prevent heart diseases. These changes eventually become maladaptive, leading to unfavorable ventricular remodeling and heart failure through aberrant activation of signaling pathways. In response to pathological stimuli such as biomechanical stress resulting from hypoxia, cardiomyocytes modify their morphology, increase protein synthesis, and reactivate cardiac fetal genes. The NO oxidizes myoglobin, thus decreasing mitochondrial oxygen supply, and inhibits mitochondrial respiration. Although eNOS responses are reduced in congestive heart failure, ischemic preconditioning induces iNOS expression, resulting in high and sustained levels of NO. In addition, it is widely accepted that in both type 1 and type 2 diabetes, there is an endothelial nitric oxide synthase (eNOS) activity impairment, resulting in diminished nitric oxide (NO) bioavailability and consequently in vascular alterations. Cardiomyocytes synthetize and secrete adiponectin, an adipocytokine that regulates glucose and fatty acid metabolism and exerts antioxidant and anti-inflammatory effects, to protect against myocardial ischemic and reperfusion injuries. These changes, in turn, contribute to the development of ventricular dysfunction. Diabetes is strongly associated with an increased incidence of heart failure, directly promoting cardiac hypertrophy, fibrosis, and apoptosis. The association between diabetes and cardiovascular and cerebrovascular diseases is well known. Diabetic patient's cardiomyocytes show an idiopathic primary defect in glycolysis induction, characterized by a glucose reduction intake and utilization. In the myocardium, during ischemia, the carbohydrate aerobic oxidation is compromised, so the anaerobic metabolism of exogenous glucose becomes a relevant strategy to generate ATP. The damage induced by ischemia is related to energy failure production to satisfy the basal needs of the jeopardized myocardium. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. Furthermore, a significant cell proliferation rate increases after the 1400 W iNOS inhibitor administration was observed. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. The association between diabetes and cardiovascular diseases is well known.
0 Comments
Leave a Reply. |