Mitochondrial ROS-Mediated Metabolic and Cytotoxic Effects of Isoproterenol on Cardiomyocytes Are p53-Dependent and Reversed by Curcumin

Abstract

Acute β-adrenergic stimulation contributes to heart failure. Here, we investigated the role of p53 in isoproterenol (ISO)-mediated metabolic and oxidative stress effects on cardiomyocytes and explored the direct protective effects offered by the antioxidant nutraceutical curcumin. Differentiated H9C2 rat cardiomyocytes treated with ISO were assayed for glucose uptake, lactate release, and mitochondrial reactive oxygen species (ROS) generation. Survival was assessed by sulforhodamine B assays. Cardiomyocytes showed significantly decreased glucose uptake and lactate release, as well as increased cellular toxicity by ISO treatment. This was accompanied by marked dose-dependent increases of mitochondria-derived ROS. Scavenging with N-acetyl-L-cysteine (NAC) effectively lowered ROS levels, which completely recovered glycolytic metabolism and survival suppressed by ISO. Mechanistically, ISO reduced extracellular-signal-regulated kinase (ERK) activation, whereas it upregulated p53 expression in an ROS-dependent manner. Silencing of p53 with siRNA blocked the ability of ISO to stimulate mitochondrial ROS and suppress glucose uptake, and partially recovered cell survival. Finally, curcumin completely reversed the metabolic and ROS-stimulating effects of ISO. Furthermore, curcumin improved survival of cardiomyocytes exposed to ISO. Thus, ISO suppresses cardiomyocyte glycolytic metabolism and survival by stimulating mitochondrial ROS in a p53-dependent manner. Furthermore, curcumin can efficiently rescue cardiomyocytes from these adverse effects.

Mitochondrial Ca2+ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

“… 54 Interestingly, the cells treated with NCF maintained ΔΨm and limited mitochondrial p53 accumulation compared to hypoxic control cells. Our finding agrees with a previous study that reported that nanocurcumin treatment inhibits p53 mitochondrial translocation in primary human ventricular cardiomyocytes under hypoxic stress 30,55 …”

“…Our finding agrees with a previous study that reported that nanocurcumin treatment inhibits p53 mitochondrial translocation in primary human ventricular cardiomyocytes under hypoxic stress. 30,55 Hypoxic stress causes a dramatic increase in oxidative stress markers, that is, free radical generation, NO production, and iNOS expression, in C2C12 myoblasts. These findings demonstrate an increase in oxidative stress, which triggers the accumulation of AOPP, resulting in cellular stress in response to hypoxic insult.…”

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

“…5A and B) highlighted that while ROS-driven TP53 activation significantly affects cardiomyocyte hypertrophy and apoptosis monotonically, reactions regulating ROS generation and scavenging exhibited nonlinear, variable impacts on the cardiomyocyte phenotype. Prior research suggests that ROS-mediated TP53 activation can drive cardiomyocyte metabolic remodeling [72] and transition from adaptive cardiac hypertrophy to maladaptive cardiac dysfunction via pro-apoptotic and anti-angiogenesis functions of TP53 [47]. Our context-specific analysis highlighted considerable variability in reactions at both upstream (e.g., NOX4 => ROS) and downstream of ROS (e.g., ROS => CaMK) across different HCM mutations and species (refer to Fig.…”

Histopathological Evaluation of Ameliorated Effect of Citric Acid on Infarcted Myocardium

“…It is a nonselective β-receptor agonist and is frequently used in intervention trails to induce ischemia and infarction of myocardium 11 . Being β-receptor agonist, it is positive ionotropic as well as chronotropic on myocardium that increase workload thus oxygen demand of myocardium 12,13 . This ultimately leads to ischemia and infarction.…”