JOURNAL ARTICLE

Sirtuin-6 inhibits cardiac fibroblasts differentiation into myofibroblasts via inactivation of nuclear factor κB signaling

Kunming Tian, Zhiping Liu, Jiaojiao Wang, Suowen Xu, Tianhui You, Peiqing Liu
Translational Research: the Journal of Laboratory and Clinical Medicine 2015, 165 (3): 374-86
25475987
Differentiation of cardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis that contributes to pathologic cardiac remodeling. However, regulation of this phenotypic transformation remains elusive. Here, we show that sirtuin-6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylase, plays a role in the regulation of myofibroblast differentiation. SIRT6 expression was upregulated under pathologic conditions in angiotensin II (Ang II)-stimulated CFs and in myocardium of rat subjected to abdominal aortic constriction surgery. SIRT6 depletion by RNA interference (small interfering RNA [siRNA]) in CFs resulted in increased cell proliferation and extracellular matrix deposition. Further examination of SIRT6-depleted CFs demonstrated significantly higher expression of α-smooth muscle actin (α-SMA), the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbated Ang II-induced myofibroblast differentiation. Overexpression of SIRT6 restored α-SMA expression in SIRT6-depleted or Ang II-treated CFs. Moreover, SIRT6 depletion induced the DNA binding activity and transcriptional activity of nuclear factor κB (NF-κB). Importantly, using an NF-κB p65 siRNA or pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB activity, reversed the expression of phenotypic markers of myofibroblasts. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of CFs to myofibroblasts.

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