Abstract 13323: Transgenic Overexpression of Snf1-Related Kinase in the Heart Improves Cardiac Metabolic Efficiency and Resistance to Myocardial Ischemia
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 metabolism.
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 and ATP were maintained, and in vivo echocardiography showed normal cardiac contractility, demonstrating that SNRK TG mice have increased metabolic efficiency. Consistent with improved metabolic efficiency, SNRK TG mice had decreased infarct size compared to wild type littermates (14.35% vs. 20.63% total ventricle area, p=0.023, n=6) following coronary ligation for seven days. Mitochondria from SNRK TG mice had enhanced state 3 respiration but no change in electron transport complex activity, and an increased respiratory control ratio (state 3/state 4 respiration), indicating reduced mitochondrial uncoupling. Uncoupling protein (UCP)-2 and 3 levels were also decreased. To identify the mechanism for the effects of SNRK on metabolic flux, we performed a yeast two hybrid screen with SNRK bait. Tribbles homolog 3 (Trb3), an Akt inhibitor, was identified as a SNRK-interacting protein, which was verified in mammalian cells. Trb3 protein levels were increased in SNRK TG mice, and phosphorylation of Akt and its substrate GSK3 was reduced. SNRK TG mice also displayed decreased mRNA levels of genes involved in glucose metabolism (including glucose transporter 1 and 4, hexokinase II, and phosphofructokinase) and fatty acid metabolism (including peroxisome proliferator-activated receptor (PPAR) α and its target proteins).
Conclusions: Our results demonstrate that SNRK increases cardiac metabolic and mitochondrial efficiency and resistance to myocardial infarct damage.
- © 2012 by American Heart Association, Inc.