Vericiguat attenuates myocardial fibrosis and Ang Ⅱ-induced cardiac fi-broblast collagen synthesis in spontaneously hypertensive rats by inhibiting P70S6K phosphorylation
10.3969/j.issn.1000-4718.2025.04.003
- VernacularTitle:维立西呱通过抑制P70S6K磷酸化减轻自发性高血压大鼠心肌纤维化及Ang Ⅱ诱导的心脏成纤维细胞胶原合成
- Author:
Dengwei WANG
1
;
Huajun WANG
;
Ying HAN
Author Information
1. 福建省疾病预防控制中心慢性病防治研究室,福建 福州 350012
- Publication Type:Journal Article
- Keywords:
vericiguat;
spontaneously hypertensive rats;
myocardial fibrosis;
angiotensin Ⅱ;
P70 ribosomal S6 kinase
- From:
Chinese Journal of Pathophysiology
2025;41(4):645-652
- CountryChina
- Language:Chinese
-
Abstract:
AIM:To investigate the effects of vericiguat(Ver)on inhibiting myocardial fibrosis and on myo-cardial angiotensin Ⅱ(Ang Ⅱ)type 1 receptor(AT1R)/P70 ribosomal S6 kinase(P70S6K)expression in spontaneously hypertensive rats(SHR).METHODS:Eight 3-month-old male Wistar-Kyoto(WKY)rats were used as the normal con-trol(WKY group),and 24 age-and sex-matched SHR were randomly and equally divided into SHR group,SHR+Ver1 group(Ver:1 mg·kg-1·d-1)and SHR+Ver3 group(Ver:3 mg·kg-1·d-1).Ver was administered via oral gavage at the cor-responding dose for 3 months.Blood pressure of rats was measured by tail-cuff method.Whole heart mass index(HMI)and left ventricular mass index(LVMI)were measured by weighing method.Myocardial collagen deposition was observed by Sirius red staining.Cardiac fibroblasts(CFBs)were cultured by tissue patch method and induced with angiotensin Ⅱ(Ang Ⅱ),followed by cellular intervention with Ver,nicorandil(Nic)or P70S6K inhibitor.The levels of collagen type Ⅰ(Col Ⅰ)and Col Ⅲ were determined by ELISA.The levels of Ang Ⅱ and cyclic guanylate cyclase(cGMP)were measured by radioimmunoassay.Western blot was performed to determine the protein levels of AT1R,P70S6K and p-P70S6K.RE-SULTS:Compared with WKY group,systolic blood pressure(SBP),diastolic blood pressure(DBP),HMI,LVMI,col-lagen volume fraction(CVF)and myocardial Col Ⅰ and Col Ⅲ in SHR group were increased(P<0.05).Compared with SHR group,HMI,LVMI,CVF and myocardial Col Ⅰ and Col Ⅲ in SHR+Ver1 group and SHR+Ver3 group were de-creased(P<0.05).The levels of plasma Ang Ⅱ,myocardial Ang Ⅱ,AT1R and p-P70S6K of myocardial tissue in SHR group were significantly higher than those of WKY group(P<0.05).Compared with SHR group,the p-P70S6K level in SHR+Ver1 group and SHR+Ver3 group was decreased(P<0.05).Compared with WKY group,myocardial cGMP level in SHR group was decreased(P<0.05).Compared with SHR group,cGMP level in SHR+Ver1 group and SHR+Ver3 group was increased(P<0.05).Ver(10-7～10-5 mol/L)could reduce the level of Ang Ⅱ-induced CFBs Col Ⅰ and Col Ⅲ synthesis in a concentration-dependent manner.Compared with the Ang Ⅱ(10-6 mol/L)group,the levels of Col Ⅰ and Col Ⅲ in CFBs in Ang Ⅱ(10-6 mol/L)+Ver(10-5 mol/L)group were significantly reduced(P<0.05).Ver(10-5 mol/L),Nic(10-4 mol/L)and P70S6K inhibitor(10-4 mol/L)could all significantly reduce the level of p-P70S6K,Col Ⅰ and Col Ⅲ in CFBs induced by Ang Ⅱ(10-6 mol/L)(P<0.05).CONCLUSION:Vericiguat can attenuate cardiac fibrosis by increasing cGMP,inhibiting SHR myocardial P70S6K phosphorylation and collagen synthesis in Ang Ⅱ-induced CFBs.
