Regulation of Cell Cycle Regulators by SIRT1 Contributes to Resveratrol-Mediated Prevention of Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in rheumatic diseases. Vascular remodeling due to the proliferation of pulmonary arterial smooth muscle cells (PASMCs) is central to the development of PAH. To date, it is still unclear if Silence Information Regulator 1 (SIRT1) regulates cell cycle regulators in the proliferation of PASMCs and contributes to prevention of PAH by resveratrol. In this study, we found that a significant decrease of SIRT1 expression levels in platelet-derived growth factor BB (PDGF-BB) treated human PASMCs (HPASMCs) and in monocrotaline (MCT) induced PAH rat. Overexpression of SIRT1 induced G1 phase arrest and increased p21 expression but decreased cyclin D1 expression in PDGF-BB treated HPASMCs. Moreover, resveratrol attenuated pulmonary arterial remodeling, decreased pulmonary arterial pressure, and upregulated SIRT1 and p21 expression but downregulated cyclin D1 expression in MCT induced PAH rat. Notably, knockdown of SIRT1 eliminated the regulation of resveratrol on p21 and cyclin D1 expression in PDGF-BB treated HPASMCs. These results demonstrated that SIRT1 mediated the regulation of resveratrol on the expression of cell cycle regulatory molecules. It suggests that SIRT1 exerts a protective role in PAH associated with rheumatic diseases and can be a potential treatment target.
Department of Rheumatology, Peking Union Medical College Hospital, Beijing 100032, China.
Shuang
S
Zhou
Department of Rheumatology, Peking Union Medical College Hospital, Beijing 100032, China.
Meng-Tao
MT
Li
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Yu-Yan
YY
Jia
Department of Rheumatology, Peking Union Medical College Hospital, Beijing 100032, China.
Jin-Jing
JJ
Liu
Department of Rheumatology, Peking Union Medical College Hospital, Beijing 100032, China.
Qian
Q
Wang
Department of Cardiology, Peking Union Medical College Hospital, Beijing 100730, China.
Zhuang
Z
Tian
Department of Cardiology, Peking Union Medical College Hospital, Beijing 100730, China.
Yong-Tai
YT
Liu
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Hou-Zao
HZ
Chen
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
De-Pei
DP
Liu
Department of Rheumatology, Peking Union Medical College Hospital, Beijing 100032, China.
Xiao-Feng
XF
Zeng
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage
D018797:Cell Cycle Proteins; D013267:Stilbenes; D014665:Vasodilator Agents; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol