Silencing Of SIRT6on Differentiation Of Cardiac Fibroblasts And Investigation The Potential Mechanisms

Objective With the development of the society,the incidence of heart failturecontinues to rise, and have became a serious public health problem. Differentiation ofcardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis thatcontributes to pathological cardiac remodeling. However, regulation of this phenotypictransformation remains elusive. Here we show that sirtuin6(SIRT6), a member of thesirtuin family of NAD+-dependent histone deacetylases, plays a critical role in theregulation of myofibroblast differentiation.Methods and Results SIRT6expression is upregulated under pathological conditionsin angiotensin II (Ang II)-stimulated CFs and in rats undergoing abdominal aorticconstriction (AAC) surgery. SIRT6depletion by RNA interference (siRNA) in CFs resultedin increased cell proliferation and extracellular matrix (ECM) deposition. Furtherexamination of SIRT6-depleted CFs demonstrated significantly higher expression ofα-smooth muscle actin (α-SMA), the classical marker for myofibroblast differentiation, andincreased formation of focal adhesions. Notably, SIRT6depletion further exacerbated AngII induced myofibroblast differentiation.. Moreover, SIRT6depletion induced the phosphorylation, nuclear translocation, DNA binding activity and transcriptional activity ofnuclear factor-κB (NF-κB) p65subunit.Conclution Our findings unravel a novel role of SIRT6as a key modulator in thephenotypic conversion of CFs to myofibroblasts, and suggest that SIRT6may be a potentialtherapeutic target in cardiac fibrosis.