Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation

PLOS ONE, Dec 2019

Cardiac fibroblasts (CFs) phenotypic conversion to myofibroblasts (MFs) represents a crucial event in cardiac fibrosis that leads to impaired cardiac function. However, regulation of this phenotypic transformation remains unclear. Here, we showed that sirtuin-7 (Sirt7) plays an important role in the regulation of MFs differentiation. Sirt7 expression and phosphorylation were upregulated in CFs upon angiotensin-II (Ang-II) stimulation. Sirt7 depletion by siRNA in CFs resulted in decreased cell proliferation and extracellular matrix (ECM) deposition. Further, examination of Sirt7-depleted CFs demonstrated significantly lower expression of α-smooth muscle actin (α-SMA), the classical marker of MFs differentiation, and decreased formation of focal adhesions. Moreover, overexpression of Sirt7 increased α-SMA expression in Ang-II treated CFs and exacerbated Ang-II-induced MFs differentiation. Moreover, Sirt7 depletion could largely reverse Ang-II induced increase of nuclear translocalization and activity of smad2 and extracellular regulated kinases (ERK) in CFs. Importantly, the increased differentiation of CFs to MFs was also abolished by smad2 siRNA or U0126. Our findings reveal a novel role of Sirt7 and its phosphorylation in the phenotypic conversion of CFs to MFs and might lead to the development of new therapeutic and prognostic tools for cardiac fibrosis.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0178530&type=printable

Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation

et al. (2017) Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation. PLoS ONE 12(6): e0178530. https://doi.org/ 10.1371/journal.pone.0178530 Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation Haichen Wang 1 2 Shengwu Liu 2 Shengqiang Liu 0 2 Wei Wei 2 Xiaolong Zhou 2 Fang Lin 2 Juanjuan Wang 2 Jinye Chen 2 Guodong Zhang 2 Yongbing Pang 2 0 Department of Cardiology, Ankang Central Hospital , Ankang, Shaanxi , China , 4 Department of Neurosurgery, Affiliated Hospital of Yan'an University , Yan'an, Shaanxi , China , 5 Department of Neurosurgery, Baoji Central Hospital , Baoji, Shaanxi , China , 6 Department of Geriatrics, Affiliated Hospital of Yan'an University , Yan'an, Shaanxi , China , 7 Department of Cardiovascular and Pulmonary, Ankang Central Hospital , Ankang, Shaanxi , China , 8 Department of Brain Tumor, Baoji Central Hospital , Baoji, Shaanxi , China 1 Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi , China , 2 Department of Neurology, Affiliated Hospital of Yan'an University , Yan'an, Shaanxi , China 2 Editor: Michael Bader, Max Delbruck Centrum fur Molekulare Medizin Berlin Buch , GERMANY Cardiac fibroblasts (CFs) phenotypic conversion to myofibroblasts (MFs) represents a crucial event in cardiac fibrosis that leads to impaired cardiac function. However, regulation of this phenotypic transformation remains unclear. Here, we showed that sirtuin-7 (Sirt7) plays an important role in the regulation of MFs differentiation. Sirt7 expression and phosphorylation were upregulated in CFs upon angiotensin-II (Ang-II) stimulation. Sirt7 depletion by siRNA in CFs resulted in decreased cell proliferation and extracellular matrix (ECM) deposition. Further, examination of Sirt7-depleted CFs demonstrated significantly lower expression of α-smooth muscle actin (α-SMA), the classical marker of MFs differentiation, and decreased formation of focal adhesions. Moreover, overexpression of Sirt7 increased αSMA expression in Ang-II treated CFs and exacerbated Ang-II-induced MFs differentiation. Moreover, Sirt7 depletion could largely reverse Ang-II induced increase of nuclear translocalization and activity of smad2 and extracellular regulated kinases (ERK) in CFs. Importantly, the increased differentiation of CFs to MFs was also abolished by smad2 siRNA or U0126. Our findings reveal a novel role of Sirt7 and its phosphorylation in the phenotypic conversion of CFs to MFs and might lead to the development of new therapeutic and prognostic tools for cardiac fibrosis. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Competing interests: The authors have declared that no competing interests exist. 1. Introduction Heart disease affects increasingly people all over the world [ 1 ]. In some forms of heart disease, including myocardial infarction, cardiomyopathies and hypertensive heart disease, fibrosis constitutes one of the most important responses of the heart to some pathological stimuli [ 2 ]. In the occurrence and development of cardiac fibrosis, cardiac fibroblasts (CFs) and their internal regulating signaling pathways play an important role. CFs consist of approximately 60% of the cardiac cells population and play a key role as mediators in normal and pathological cardiac remodeling [ 3 ]. The persistent activation of CFs is identified by increased proliferation and subsequent extracellular matrix (ECM) secretion which contribute to maintain the structural integrity of heart [ 4 ]. Despite the fact that these changes are an important reparative wound healing response, they may become a prime cause for the accumulation of collagen and cardiac fibrosis if they last for a prolonged activation [ 5 ]. Therefore, many studies pointed specifically on its role in fibrosis [ 6 ]. In the process of promoting cardiac fibrosis, CFs could differentiate into myofibroblasts (MFs), a cell type which can secrete ECM components, that produces Ang-II and a variety of fibrogenic growth factors (FGF) and transforming-growth factor β (TGF-β) [ 7 ]. Furthermore, MFs can express contractile proteins, including α-smooth muscle actin (α-SMA), indicating acquisition of MFs phenotype [ 8 ]. Researches have demonstrated that CFs expressed some specific integrins, in which collagen and fibronectin are the primary ligand [ 9 ]. Not only integrin participate in the process, but also Ang-I receptor has been shown to be mechanically activated both in vitro and in vivo in the absence of angiotensin-II (Ang-II) [ 10 ] resulting in increasing ECM components, matrix metalloproteinases (MMPs) and integrin signaling in CFs [ 11 ]. Although there are many studies focused on cardiac fibrosi (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0178530&type=printable

Haichen Wang, Shengwu Liu, Shengqiang Liu, Wei Wei, Xiaolong Zhou, Fang Lin, Juanjuan Wang, Jinye Chen, Guodong Zhang, Yongbing Pang. Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-II stimulation, PLOS ONE, 2017, Volume 12, Issue 6, DOI: 10.1371/journal.pone.0178530