Abstract P237: Exercise Training Prevents Hypercholesterolemia-Induced Cardiac Mitochondrial Dysfunction

Abstract

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We hypothesized that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response, and that exercise training could reverse this phenotype. FH pigs were obtained from the University of Wisconsin. Control, normolipidemic farm pigs were maintained on standard pig chow. After 4 months on a high-fat diet, the FH pigs were switched to the standard pig chow, and randomized to sedentary or exercise groups. The exercise group underwent a progressive treadmill-based training program for 4 months. At the end of the training protocol the animals were sacrificed and the heart removed. MPT was assessed by mitochondrial swelling in response to Ca2+. Protein nitrotyrosylation, GSH levels, and antioxidant enzyme expression were also examined. FH pigs did show an increased MPT response despite no change in the expression of putative MPT pore components adenine nucleotide translocase (ANT), mitochondrial phosphate carrier (PiC), and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation and decreased GSH levels. This was associated with concomitant decreases in the expression of mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin-2 (Trx2). However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce oxidative stress, and increase MnSOD expression. We conclude that hypercholesterolemia causes increased oxidative stress and enhances the MPT response in the porcine myocardium, and that exercise training can correct for both the increased oxidative stress and MPT alterations observed with hypercholesterolemia.