Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart

• Published in: Life sciences (1973) 2015-11, Vol.141, p.170-178
• Main Authors: Shi, Jianru, Dai, Wangde, Hale, Sharon L., Brown, David A., Wang, Miao, Han, Xianlin, Kloner, Robert A.
• Format: Article
• Language: English
• Subjects: Animals; Bendavia; Cardiolipins - metabolism; Cardioprotection; Collagen - biosynthesis; Collagen - genetics; Energy Metabolism - drug effects; Energy Metabolism - genetics; Fatty Acids - metabolism; Female; Fibrosis; Gene Expression - drug effects; Glucose - metabolism; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocardium - pathology; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases - biosynthesis; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - genetics; Ventricular Remodeling - drug effects
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2015.09.022

We have observed that Bendavia, a mitochondrial-targeting peptide that binds the phospholipid cardiolipin and stabilizes the components of electron transport and ATP generation, improves cardiac function and prevents left ventricular remodeling in a 6week rat myocardial infarction (MI) model. We hypothesized that Bendavia restores mitochondrial biogenesis and gene expression, suppresses cardiac fibrosis, and preserves sarco/endoplasmic reticulum (SERCA2a) level in the noninfarcted border zone of infarcted hearts. Starting 2h after left coronary artery ligation, rats were randomized to receive Bendavia (3mg/kg/day), water or sham operation. At 6weeks, PCR array and qRT-PCR was performed to detect gene expression. Picrosirius red staining was used to analyze collagen deposition. There was decreased expression of 70 out of 84 genes related to mitochondrial energy metabolism in the border zone of untreated hearts. This down-regulation was largely reversed by Bendavia treatment. Downregulated mitochondrial biogenesis and glucose & fatty acid (FA) oxidation related genes were restored by administration of Bendavia. Matrix metalloproteinase (MMP9) and tissue inhibitor of metalloproteinase (TIMP1) gene expression were significantly increased in the border zone of untreated hearts. Bendavia completely prevented up-regulation of MMP9, but maintained TIMP1 gene expression. Picrosirius red staining demonstrated that Bendavia suppressed collagen deposition within border zone. In addition, Bendavia showed a trend toward restoring SERCA2a expression. Bendavia restored expression of mitochondrial energy metabolism related genes, prevented myocardial matrix remodeling and preserved SERCA2a expression in the noninfarcted border, which may have contributed to the preservation of cardiac structure and function.