L-Carnitine and Resveratrol Action on Oxidative Response and Differentiation in H9c2 Rat Cardiomyocytes

Abstract

Diabetic heart disease (DHD) results in structural and functional deterioration due to progressive loss of cardiomyocytes and cardiac stem cells, leading to a premature aging of the diabetic heart. The causes of DHD development are not completely clarified, but it is evident that higher oxidative stress of diabetes induces cardiac structural alterations. Recently, the use of stem cells or cardiac progenitors have inspired the most promising therapeutic strategies but these approaches are limited in diabetic patients. Herein we investigate L-Carnitine (LC) and Resveratrol (RSV) actions on oxidative stress and differentiation process in H9c2 rat cardiomyocytes. H9c2, during proliferation or differentiation condition, were treated with LC (0.5 or 5mM) or RSV (0.1 or 25μM). LC significantly enhanced anti-oxidative response by increasing (48 and 72h) mitochondrial SOD2 protein expression and STAT3 activation. LC did not induce p21 translocation at the nuclear level, demonstrating not to have an inhibitory effect on the cell cycle. LC decreased protein synthesis of CaMKII, whose activation is associated with hypertrophic process. In addition, the protective LC effect on H9c2 cardiomyocytes in stress condition was evaluated treating cells with LC 48h before exposure to H2O2: LC significantly reduced intracellular ROS concentration in a dose-dependent manner. RSV 0.1μM while increasing CaMKII content, did not show any effect on the proliferative potential of H9c2. RSV 25μM induced a significant proliferation decrease in favor of H9c2 differentiation, as shown by ERKs pathway activation and α-actinin protein synthesis promotion. RSV 25μM significantly reduced ROS generation induced by rotenone in neo cardiomyotubes (72h). The ability to improve the microenvironment damaged by oxidative stress and to stimulate cardiac progenitor differentiation could recognize LC/RSV as valid adjuvant therapies to preserve cardiomyocytes survival and ameliorate heart regeneration. Disclosure I. Terruzzi: None. P. Senesi: None. A. Montesano: None. F. Vacante: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.