Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF‐κB‐dependent transcriptional activity

Abstract

BACKGROUND AND PURPOSESirtuin 6 (SIRT6) is involved in regulation of glucose and fat metabolism. However, its possible contribution to cardiac dysfunction remains to be determined. In the present study, the effect of SIRT6 on cardiac hypertrophy induced by angiotensin II (AngII) and the underlying molecular mechanisms were investigated. EXPERIMENTAL APPROACHThe expression and deacetylase activity of SIRT6 were measured in hypertrophic cardiomyocytes induced by AngII. After SIRT6 overexpression by transfection, or depletion by RNA interference in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Further, the interaction between SIRT6 and the transcription factor NF-kB was investigated by co-immunoprecipitation, confocal immunofluorescence microscopy and luciferase reporter gene assay. The expression and deacetylase activity of SIRT6 were measured in vivo, using the abdominal aortic constriction (AAC) model of cardiac hypertrophy in rats. KEY RESULTSIn AngII-induced hypertrophic cardiomyocytes and also in AAC-induced hypertrophic hearts, the expression of SIRT6 protein was upregulated, while its deacetylase activity was decreased. Overexpression of wild-type SIRT6 but not its catalytically inactive mutant, attenuated AngII-induced cardiomyocyte hypertrophy. We further demonstrated a physical interaction between SIRT6 and NF-kB catalytic subunit p65, whose transcriptional activity could be repressed by SIRT6 overexpression. CONCLUSIONS AND IMPLICATIONSOur findings suggest that SIRT6 suppressed cardiomyocyte hypertrophy in vitro via inhibition of NF-kB-dependent transcriptional activity and that this effect was dependent on its deacetylase activity.

A Proteomic Perspective of Sirtuin 6 (SIRT6) Phosphorylation and Interactions and Their Dependence on Its Catalytic Activity

“…These associations comprised diverse transcription factors, such as the major transcription regulator tumor suppressor p53, Bcl-2-associated transcription factor 1 (BCLAF1), tyrosine-protein kinase BAZ1B, tripartite motif-containing protein 27 (TRIM27), and NF--B-repressing factor (NKRF). While SIRT6 is known to regulate DNA damage repair (35)(36)(37) and NF--B-mediated gene expression (26,30), our results provide evidence of previously unknown SIRT6 associations with factors involved in these processes. Moreover, interactions observed in the absence of stress stimulation highlight the importance of characterizing SIRT6 binding partners under normal conditions.…”

“…telomeres) to maintain chromatin integrity (25,28,29) or regulate gene expression via recruitment by transcription factors (e.g. NFkB, HIF1␣) (26,30,31). This catalytic activity was shown to be diminished upon the mutation of histidine 133 (H133), a residue conserved among all seven human sirtuins (1,9,25,32).…”

From Sirtuin Biology to Human Diseases: An Update

“…In models of cardiac hypertrophy, Sirt6 expression is up-regulated, yet its deacetylase activity is reduced (88). Increased activity of SIRT6 protects cardiomyocytes from a hypertrophic response in vitro by suppressing NF-B activation (88). Furthermore, increased NAD synthesis protects cardiomyocytes from hypertrophy, possibly through SIRT6 activation (89).…”

“…In models of cardiac hypertrophy, Sirt6 expression is up-regulated, yet its deacetylase activity is reduced (88). Increased activity of SIRT6 protects cardiomyocytes from a hypertrophic response in vitro by suppressing NF-B activation (88).…”

Changes in gene expression in SIRT3 knockout liver cells

“…There is evidence that SIRTs regulate a number of different transcription factors such as FOXO (Jacobs et al, 2008), p53 (Peck et al, 2010), and NFkB (Yu et al, 2013), though it is not clear whether SIRT3 alters the gene expression profile of the cell. Thus, we are further interested in how SIRT3 may regulate the gene expression of different transcription factors important in cancer pathways in addition to genes important in cellular metabolism.…”