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Cardiomyocyte-Specific Snrk Prevents Inflammation in the Heart. J Am Heart Assoc 2019 11 19;8(22):e012792

Date

11/14/2019

Pubmed ID

31718444

Pubmed Central ID

PMC6915262

DOI

10.1161/JAHA.119.012792

Scopus ID

2-s2.0-85075040816   2 Citations

Abstract

Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in Snrk cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for Snrk in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for Snrk in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased in Snrk knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for Snrk in CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2+ macrophages was observed in basal and Ang II-infused states. In vitro analysis of Snrk knockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in Snrk knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.

Author List

Thirugnanam K, Cossette SM, Lu Q, Chowdhury SR, Harmann LM, Gupta A, Spearman AD, Sonin DL, Bordas M, Kumar SN, Pan AY, Simpson PM, Strande JL, Bishop E, Zou MH, 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
Pippa M. Simpson PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Andrew Spearman MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




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