Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: Beneficial effects of chronic exercise

Kyle S. McCommis, Allison M. McGee, M. Harold Laughlin, Douglas K. Bowles, Christopher P. Baines

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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 tested the hypothesis that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response and that exercise training could reverse this phenotype. MPT was assessed by mitochondrial swelling in response to 10-100 μM Ca 2+. FH pigs did show an increased MPT response to Ca 2+ that was associated with decreases in the expression of the putative MPT pore components mitochondrial phosphate carrier (PiC) and cyclophilin- D (CypD). FH also caused increased oxidative stress, depicted byincreased protein nitrotyrosylation, as well as decreased levels of reduced GSH in cardiac mitochondria. Expression of the mitochondrial antioxidant enzymes manganese superoxide dismutase (Mn- SOD), thioredoxin-2 (Trx2), and peroxiredoxin-3 (Prx3) was greatly reduced in the FH pigs. In contrast, cytosolic catalase expression and activity were increased. However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce mitochondrial oxidative stress, and return MnSOD, Trx2, Prx3, and catalase expression/ activities to normal. We conclude that FH reduces mitochondrial antioxidants, increases mitochondrial oxidative stress, and enhances the MPT response in the porcine myocardium, and that exercise training can reverse these detrimental alterations.

Original languageEnglish
Pages (from-to)R1250-R1258
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume301
Issue number5
DOIs
StatePublished - Nov 2011

Keywords

  • Antioxidant proteins
  • Exercise training
  • Familial hypercholesterolemia

Fingerprint

Dive into the research topics of 'Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: Beneficial effects of chronic exercise'. Together they form a unique fingerprint.

Cite this