Abstract 14929: Transgenic Overexpression of Snf1-Related Kinase in the Heart Improves Cardiac Metabolic Efficiency Through UCP3 Downregulation and a Reduction in Mitochondrial Uncoupling
Introduction: Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase, but its function is unknown. We found that SNRK is increased in hearts from patients with ischemic cardiomyopathy, and our gene array data suggested that SNRK alters metabolic genes. Here, we assessed the hypothesis that SNRK regulates cardiac metabolic efficiency.
Results: Transgenic (TG) mice with cardiac-specific overexpression of SNRK were generated, and displayed decreased glycolysis (1267.66 vs. 1925.60 nmol/min/g, p=0.004, n=6), glucose oxidation (441.73 vs. 602.68 nmol/min/g, p=0.068), and palmitate oxidation (262.39 vs. 385.07 nmol/min/g, p=0.005) compared to wild type littermate controls in perfused working hearts. However, cardiac power, contractility, ATP, and triglyceride and glycogen stores were maintained, while oxygen consumption was reduced, suggesting that SNRK TG mice have increased metabolic efficiency. Consistent with improved metabolic efficiency, SNRK TG mice exhibited decreased infarct size relative to area-at-risk (50.08% vs. 31.99%, p=0.046, n=4) 48 hours after ischemia/reperfusion injury. Mitochondria from SNRK TG mice had reduced state 4 respiration, an improved respiratory control ratio (state 3/state 4 respiration), and increased mitochondrial membrane potential, but had no change in electron transport chain complex activity, indicating reduced mitochondrial uncoupling. Uncoupling protein 3 (UCP3) levels were also decreased. Opposite to SNRK overexpression, SNRK knockdown in HL-1 cardiac cells resulted in increased oxygen consumption, mitochondrial depolarization, fatty acid oxidation, and UCP3 levels. Combined knockdown of UCP3 with SNRK reversed these effects, suggesting that UCP3 is needed for the effects of SNRK on metabolism.
Conclusions: Our results demonstrate that SNRK increases cardiac metabolic and mitochondrial efficiency through reductions in UCP3 and mitochondrial uncoupling.
- © 2013 by American Heart Association, Inc.