Cardiomyocyte specific peroxisome proliferator-activated receptor-α overexpression leads to irreversible damage in ischemic murine heart

• Published in: Life sciences (1973) 2014-05, Vol.102 (2), p.88-97
• Main Authors: Duerr, Georg D., Heinemann, Jan C., Arnoldi, Vanessa, Feisst, Andreas, Kley, Julian, Ghanem, Alexander, Welz, Armin, Dewald, Oliver
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Death - genetics; Chemokines; Diabetes; Female; Gene Expression Regulation; Inflammation; Ischemia/reperfusion; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Ischemia - genetics; Myocardial Ischemia - metabolism; Myocardial Ischemia - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; PPAR alpha - biosynthesis; PPAR alpha - genetics; PPAR-α; Remodeling
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2014.03.019

Peroxisome proliferator-activated receptor (PPAR)-α is downregulated in ischemic myocardium resulting in substrate switch from fatty acid oxidation to glucose utilization. Pharmacological PPAR-α activation leads to increased fatty acid oxidation and myocardial lipotoxicity. The aim of our study was to investigate the role of cardiomyocyte specific PPAR-α overexpression in myocardial adaptation to repetitive ischemic injury without myocardial infarction. Repetitive, brief I/R was performed in male and female MHC-PPAR-α overexpressing and wildtype-C57/Bl6 (WT)-mice, age 10–12weeks, for 3 and 7 consecutive days. After echocardiography, their hearts were excised for histology and gene/protein-expression measurements (Taqman/Western blot). MHC-PPAR-α mice developed microinfarctions already after 3days of repetitive I/R in contrast to interstitial fibrosis in WT-mice. We found higher deposition of glycogen, increased apoptosis and dysfunctional regulation of antioxidative mediators in MHC-PPAR-α mice. MHC-PPAR-α mice presented with maladaptation of myosin heavy chain isoforms and worse left ventricular dysfunction than WT-mice. We found prolonged, chemokine-driven macrophage infiltration without induction of proinflammatory cytokines in MHC-PPAR-α mice. Persistent accumulation of myofibroblasts in microinfarctions indicated active remodeling resulting in scar formation in contrast to interstitial fibrosis without microinfarctions in WT-mice. However, MHC-PPAR-α hearts had only a weak induction of tenascin-C in contrast to its strong expression in WT-hearts. Cardiomyocyte-specific PPAR-α overexpression led to irreversible cardiomyocyte loss with deteriorated ventricular function during brief, repetitive I/R episodes. We identified higher glycogen deposition, increased apoptosis, deranged antioxidative capacity and maladaptation of contractile elements as major contributors involved in the modulation of post-ischemic inflammation and remodeling.