Abstract 11: Transgenic Overexpression of Snf1-Related Kinase in the Heart Improves Cardiac Metabolic Efficiency and Response to Myocardial Ischemia

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Introduction: Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated kinase. The function and substrates of SNRK are unknown. We have found that SNRK is upregulated in hearts from patients with ischemic cardiomyopathy, and our previous gene array data suggested that SNRK alters metabolic gene expression. Here, we assessed the hypothesis that SNRK regulates cardiac metabolism. Results: SNRK transgenic mice with specific overexpression of SNRK in the heart displayed decreased glycolysis (1267.66 vs. 1925.60 nmol/min/g dhw, p=0.004, n=6), glucose oxidation (441.73 vs. 602.68 nmol/min/g dhw, p=0.068, n=6), and palmitate oxidation (262.39 vs. 385.07 nmol/min/g dhw, p=0.005, n=6) compared to wild type littermate controls in perfused working hearts. However, cardiac power output and function were maintained, demonstrating that SNRK transgenic mice have increased metabolic efficiency. Mitochondria isolated from SNRK transgenic mice had increased state 3 respiration and oxidative capacity, along with an increased respiratory control ratio (state 3/state 4 respiration), indicating reduced mitochondrial uncoupling. 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 inhibitor of Akt, was identified as a SNRK-interacting protein, which was verified by co-immunoprecipitation and mammalian two hybrid assay. Trb3 protein levels were increased in the SNRK transgenic mice, and phosphorylation of Akt and its substrate GSK3 was reduced. SNRK transgenic mice also had decreased mRNA levels of glucose transporter 1 and 4, hexokinase II, and phosphofructokinase. Additionally, mRNA levels of the fatty acid metabolism regulators peroxisome proliferator-activated receptor (PPAR) α and PPARγ were reduced, as well as their targets uncoupling protein 2 and 3. Finally, SNRK transgenic mice had decreased infarct size compared to wild type littermates (14.35% vs. 20.63% total left ventricle area, p=0.023, n=6) following myocardial infarction for seven days. Conclusions: Our results demonstrate that SNRK increases cardiac metabolic and mitochondrial efficiency and resistance to myocardial infarct cell death.