Abstract 18723: Endothelial Calpain Promotes Adverse Cardiac Changes in Mice Fed a High Fat Diet by Impairing Angiogenesis
Background: In diabetes and obesity, excessive fatty acid uptake by cardiomyocytes induces adverse cardiac changes, a condition described as cardiac lipotoxicity. We recently reported that deletion of capns1 selectively in cardiomyocytes reduces lipotoxic injury and myocardial dysfunction in mice fed a high fat diet (HFD).
Aims: This study was attempted to investigate the role of endothelial calpain in adverse cardiac changes during lipotoxicity and its underlying mechanisms.
Methods and Results: Endothelial cell-specific capns1 knockout mice were generated by breeding mice bearing the targeted capns1PZ allele containing loxP sites flanking essential coding exons and mice with endothelial cell-specific expression of Cre recombinase driven by the Tie2 promoter. No adverse phenotypes were observed in capns1 knockout mice. Both capns1 knockout mice and their wild-type littermates were fed a HFD or normal diet for 12 weeks. HFD increased body weight, altered blood lipid profiles and impaired glucose tolerance comparably in both capns1 knockout mice and their wild-type littermates. Calpain activity and cardiac collagen deposition were significantly increased in HFD-fed mouse hearts, and these were accompanied by myocardial dysfunction. These effects of HFD were attenuated by disruption of endothelial calpain in capns1 knockout mice. Mechanistically, deletion of capns1 prevented a reduction in capillary density and increased coronary blood flow in HFD-fed mouse hearts. Inhibition of calpain restored their tube formation and migration of cardiac micro-vascular endothelial cells in response to palmitate, concurrent with decreased reactive oxygen species in mitochondria and increased bioavailability of nitric oxide.
Conclusions: Disruption of endothelial calpain prevents lipotoxicity-induced cardiac changes and myocardial dysfunction in mice fed a HFD. The role of calpain is mediated, at least partially, through angiogenesis impairment of cardiac micro-vascular endothelial cells and excessive mitochondrial reactive oxygen species in lipotoxic hearts. Thus, calpain may be an important therapeutic target for cardiac lipotoxicity.
Author Disclosures: T. Peng: None. X. Teng: None.
- © 2016 by American Heart Association, Inc.