Transition From Obesity to Metabolic Syndrome Is Associated With Altered Myocardial Autophagy and Apoptosis

Abstract

Objective Transition from obesity to metabolic-syndrome (MetS) promotes cardiovascular diseases, but the underlying cardiac pathophysiological mechanisms are incompletely understood. We tested the hypothesis that development of insulin resistance (IR) and MetS is associated with impaired myocardial cellular turnover. Methods and results MetS-prone Ossabaw pigs were randomized to 10 weeks of standard chow (lean), or to 10 (obese) or 14 (MetS) weeks of atherogenic diet (n=6 each). Cardiac structure, function, and myocardial oxygenation were assessed by multidetector computed-tomography and Blood-Oxygen-Level-Dependent (BOLD)-magnetic resonance imaging (MRI), the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. Both obese and MetS showed obesity and dyslipidemia, while only MetS showed IR. Cardiac output and myocardial perfusion increased only in MetS, yet BOLD-MRI showed hypoxia. Inflammation, oxidative stress, mitochondrial dysfunction, and fibrosis also increased in both obese and MetS, but more pronouncedly in MetS. Furthermore, autophagy in MetS was decreased and accompanied by marked apoptosis. Conclusions Development of IR characterizing a transition from obesity to MetS is associated with progressive changes of myocardial autophagy, apoptosis, inflammation, mitochondrial dysfunction, and fibrosis. Restoring myocardial cellular turnover may represent a novel therapeutic target for preserving myocardial structure and function in obesity and MetS.

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