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Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function. Circ Cardiovasc Genet 2016 Dec;9(6):474-486

Date

10/27/2016

Pubmed ID

27780848

Pubmed Central ID

PMC5177517

DOI

10.1161/CIRCGENETICS.116.001515

Scopus ID

2-s2.0-85007206187   7 Citations

Abstract

BACKGROUND: Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months.

METHODS AND RESULTS: We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits.

CONCLUSIONS: Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart.

Author List

Cossette SM, Bhute VJ, Bao X, Harmann LM, Horswill MA, Sinha I, Gastonguay A, Pooya S, Bordas M, Kumar SN, Mirza SP, Palecek SP, Strande JL, Ramchandran R

Authors

Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Echocardiography
Embryonic Stem Cells
Energy Metabolism
Fibrosis
Genetic Predisposition to Disease
Heart Failure
Homozygote
Human Umbilical Vein Endothelial Cells
Lipid Metabolism
Magnetic Resonance Spectroscopy
Metabolomics
Mice, Knockout
Myocytes, Cardiac
Oxidative Phosphorylation
Phenotype
Protein Kinase Inhibitors
Protein-Serine-Threonine Kinases
RNA Interference
Signal Transduction
Transfection
rho-Associated Kinases
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a