Heart failure (HF) is a major cause of morbidity and mortality in the developed world, and despite recent advances, its prevalence continues to grow. Current therapies for HF are largely directed at the neurohormonal axis, although alterations in cardiomyocyte energy metabolism are demonstrated in HF. Mammalian sucrose non-fermenting 1-related kinase (SNRK) is a serine/threonine kinase with sequence homology to AMP-activated kinases (AMPK); however, its primary function is unknown. Our lab recently demonstrated that SNRK levels are increased in response to hypoxia and in patients with cardiomyopathy, and a gene array with SNRK overexpression demonstrated that SNRK alters the levels of genes involved in metabolism. To better define the function of SNRK in cardiac metabolism, we have generated a transgenic (TG) mouse that overexpresses SNRK in the heart. SNRK TG mice display 30-50% less glucose and fatty acid oxidation despite normal cardiac function, suggesting that they are more efficient in substrate utilization. To determine the mechanism by which SNRK regulates cardiac metabolism, we have measured mitochondrial metabolism in SNRK TG mice. These results demonstrate that the levels of uncoupling protein (UCP) 3 are reduced in SNRK TG mice, while state 3/state 4 respiration is increased, suggesting improved mitochondrial coupling and efficiency. Finally, SNRK knockdown in cardiomyocytes has the opposite metabolic effects of its overexpression. The objective of this proposal is to determine the mechanism by which SNRK regulates cardiac metabolism, and to elucidate its role in protecting against HF. Our central hypothesis is that SNRK affects cardiac metabolism by reducing substrate utilization and increasing mitochondrial coupling, and that SNRK overexpression protects against the development of HF by increasing cardiac metabolic efficiency and decreasing reactive oxygen species (ROS). Our proposal incorporates three specific aims that explore our central hypothesis: Specific Aim 1. To elucidate whether SNRK alters mitochondrial function by improving mitochondrial coupling. Specific Aim 2. To determine whether SNRK is protective against the development of HF. Specific Aim 3. To determine whether SNRK alters cellular ROS levels at baseline or in response to injury.
|Effective start/end date||7/1/14 → 6/30/16|
- American Heart Association Midwest Affiliate (14POST20490097)
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