Open AccessCardiomyocyte‐Specific Snrk Prevents Inflammation in the Heart
Author(s) -
Thirugnanam Karthikeyan,
Cossette Stephanie M.,
Lu Qiulun,
Chowdhury Shreya R.,
Harmann Leanne M.,
Gupta Ankan,
Spearman Andrew D.,
Sonin Dmitry L.,
Bordas Michelle,
Kumar Suresh N.,
Pan Amy Y.,
Simpson Pippa M.,
Strande Jennifer L.,
Bishop Erin,
Zou MingHui,
Ramchandran Ramani
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.119.012792
Subject(s) - proinflammatory cytokine , gene knockdown , downregulation and upregulation , heart failure , inflammation , angiotensin ii , protein kinase b , nfkb1 , knockout mouse , medicine , microbiology and biotechnology , cancer research , context (archaeology) , signal transduction , chemistry , biology , endocrinology , biochemistry , transcription factor , apoptosis , paleontology , receptor , blood pressure , gene
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 ( CM s) 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 CM s, we also observed NF ‐κB pathway activation in CM s, and an increased presence of Mac2 + macrophages was observed in basal and Ang II –infused states. In vitro analysis of Snrk knockdown HL ‐1 CM s 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 CM s. Conclusions During heart failure, SNRK acts as a cardiomyocyte‐specific repressor of cardiac inflammation and fibrosis.