Akt/FOXO3a/SIRT1 Mediated Cardioprotection by n-Tyrosol against Ischemic Stress in Rat In vivo model of Myocardial Infarction:Switching Gears towards Survival and Longevity

摘要

Moderate consumption of wine has been associated with decreased risk of cardiovascular events. Recently we have shown that white wine is equally cardioprotective like red wine. However, unlike resveratrol (polyphenol in red wine), the white wine component, n-Tyrosol/2-(4-hydroxyphenyl) ethanol has not been explored for its cardioprotective effect and mechanism of action. Therefore, the present study was designed to evaluate the effect of tyrosol treatment (5mg/kg/day for 30 days) on myocardial ischemic stress in rat in vivo model of Myocardial Infarction (MI) and to identify key molecular targets involved in this mechanism. MI was induced by Left Anterior Descending (LAD) coronary artery ligation. We have observed reduced infarct size (% area at risk, 32.42 vs 48.03) and cardiomyocyte apoptosis (171vs 256 counts /100HPF) along with improvement in the myocardial functional parameters such as LVIDs (5.89 vs 6.58 mm), % Ejection Fraction (51.91 vs 45.09 %) and % Fractional Shortening (28.46 vs 23.52 %) as assessed by echocardiography in the tyrosol treated animals when compared to the non-treated controls. We have also observed significant, increase in the phosphorylation and activation of Akt (1.4 fold) and eNOS (3 fold), phosphorylation and inhibition of FOXO3a (2.6 fold) pro-apoptotic activity and increase in the expression of nuclear longevity protein SIRT1 (3.2 fold) in the tyrosol treated MI group as compared to the non-treated MI control. We have demonstrated for the first time that tyrosol induces myocardial protection against ischemia induced stress thereby prompting the development of a new drug to combat IHD, while also revealing potential therapeutic molecular targets such as FOXO3a and SIRT1 that can be modulated to precondition the heart to overcome an ischemic stress.