Protective Effects of Sacubitril/Valsartan on Cardiac Fibrosis and Function in Rats With Experimental Myocardial Infarction Involves Inhibition of Collagen Synthesis by Myocardial Fibroblasts Through Downregulating TGF-β1/Smads Pathway.
Protective Effects of Sacubitril/Valsartan on Cardiac Fibrosis and Function in Rats With Experimental Myocardial Infarction Involves Inhibition of Collagen Synthesis by Myocardial Fibroblasts Through Downregulating TGF-β1/Smads Pathway.
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Sacubitril/Valsartan 对实验性心肌梗死大鼠的心脏纤维化和功能的保护作用涉及通过下调 TGF-β1/Smads 途径抑制心肌成纤维细胞的胶原蛋白合成
DOI：
10.3389/fphar.2021.696472
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发表时间：
2021
影响因子：
5.6
通讯作者：
Lin L
中科院分区：
文献类型：
--
作者：
Wu M;Guo Y;Wu Y;Xu K;Lin L
目的：探讨沙库巴曲/缬沙坦对大鼠实验性心肌梗死后心肌纤维化及TGF-β1处理的心肌成纤维细胞的影响及其机制。 研究方法：对雄性Sprague-Dawley（SD）大鼠进行冠状动脉结扎以建立心肌梗死，并灌胃给予载体缬沙坦（瓦尔，32 mg/kg，每日一次）或沙库巴曲/缬沙坦（Sac/瓦尔，68 mg/kg，每日一次）4周。平行地，将从新生SD大鼠分离的心肌成纤维细胞（MF）暴露于缺氧并用TGF-β1（5 ng/ml）加媒介物、瓦尔（107-10-5 M）或Sac/瓦尔（107-105 M）处理。采用超声心动图和组织学方法分别测定大鼠心功能和纤维化程度。采用细胞计数试剂盒-8和酶联免疫吸附试验分别测定成纤维细胞的活力和胶原合成。采用免疫印迹和免疫细胞化学方法检测TGF-β1、Smad 3、磷酸化Smad 3（p-Smad 3）蛋白表达及亚细胞定位。 结果如下：Sac/瓦尔可明显改善心肌梗死后大鼠心脏结构和功能，包括降低左室舒张末期内径和室间隔厚度，增加射血分数，降低心肌胶原体积分数和Ⅰ、Ⅲ型胶原水平，且效果上级瓦尔。Sac/瓦尔对心肌TGF-β1和p-Smad 3蛋白表达的抑制作用优于瓦尔。Sac/瓦尔对TGF-β1诱导的成纤维细胞增殖、胶原合成、Smad 3磷酸化和核转位均有明显抑制作用，且作用优于瓦尔。Smad 3的过表达和沉默分别增强和逆转了Sac/瓦尔对TGF-β1诱导的MFs胶原合成的抑制作用。 结论：沙库巴曲/缬沙坦可改善实验性心肌梗死后大鼠的心功能和纤维化，其作用与抑制TGF/Smads信号通路抑制心肌成纤维细胞胶原合成有关。
Objectives: To investigate the effect and mechanism of sacubitril/valsartan on myocardial fibrosis in rats following experimental myocardial infarction and in TGF-β1-treated myocardial fibroblasts. Methods: Male Sprague-Dawley (SD) rats were subjected to coronary artery ligation to establish myocardial infarction and intragastrically fed vehicle, valsartan (Val, 32 mg/kg, once-daily) or sacubitril/valsartan (Sac/Val, 68 mg/kg, once-daily) for 4 weeks. In parallel, myocardial fibroblasts (MFs) isolated from neonatal SD rats were exposed to hypoxia and treated with TGF-β1 (5 ng/ml) plus vehicle, Val (107–10–5 M) or Sac/Val (107–105 M). Rat cardiac function and fibrosis were measured by echocardiography and histological method, respectively. MFs viability and collagen synthesis were determined by cell counting kit-8 and enzyme-linked immunosorbent assay, respectively. Protein expressions of TGF-β1, Smad3, phosphorylated Smad3 (p-Smad3), and p-Smad3 subcellular localization were detected by immunoblotting and immunocytochemistry. Results: Sac/Val significantly improved cardiac structure and function in rats after myocardial infarction, including decreased left ventricular end-diastolic diameter and interventricular septal thickness, increased ejection fraction, and reduced myocardial collagen volume fraction and type Ⅰ and type Ⅲ collagen levels, and this effect was superior to that of Val. Besides, Sac/Val inhibited myocardial TGF-β1 and p-Smad3 protein expression better than Val. Mechanically, Sac/Val significantly attenuated TGF-β1-induced proliferation and collagen synthesis of MFs, and inhibit Smad3 phosphorylation and nucleus translocation, and this effect outperformed Val. Overexpression and silencing of Smad3 enhanced and reversed the inhibitory effects of Sac/Val on TGF-β1-induced collagen synthesis by MFs, respectively. Conclusions: Sacubitril/valsartan improves cardiac function and fibrosis in rats after experimental myocardial infarction, and this effect is related to the inhibition of collagen synthesis in myocardial fibroblasts by inhibiting the TGF/Smads signaling pathway.
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影响因子：
8.3
作者：
Petrov, VV;Fagard, RH;Lijnen, PJ
通讯作者：
Lijnen, PJ
影响因子：
1.7
作者：
Shen, Xiang-Chun;Yang, Yu-Ping;Liu, Xing-De
通讯作者：
Liu, Xing-De
影响因子：
24
作者：
Roth GA;Johnson C;Abajobir A;Abd-Allah F;Abera SF;Abyu G;Ahmed M;Aksut B;Alam T;Alam K;Alla F;Alvis-Guzman N;Amrock S;Ansari H;Ärnlöv J;Asayesh H;Atey TM;Avila-Burgos L;Awasthi A;Banerjee A;Barac A;Bärnighausen T;Barregard L;Bedi N;Belay Ketema E;Bennett D;Berhe G;Bhutta Z;Bitew S;Carapetis J;Carrero JJ;Malta DC;Castañeda-Orjuela CA;Castillo-Rivas J;Catalá-López F;Choi JY;Christensen H;Cirillo M;Cooper L Jr;Criqui M;Cundiff D;Damasceno A;Dandona L;Dandona R;Davletov K;Dharmaratne S;Dorairaj P;Dubey M;Ehrenkranz R;El Sayed Zaki M;Faraon EJA;Esteghamati A;Farid T;Farvid M;Feigin V;Ding EL;Fowkes G;Gebrehiwot T;Gillum R;Gold A;Gona P;Gupta R;Habtewold TD;Hafezi-Nejad N;Hailu T;Hailu GB;Hankey G;Hassen HY;Abate KH;Havmoeller R;Hay SI;Horino M;Hotez PJ;Jacobsen K;James S;Javanbakht M;Jeemon P;John D;Jonas J;Kalkonde Y;Karimkhani C;Kasaeian A;Khader Y;Khan A;Khang YH;Khera S;Khoja AT;Khubchandani J;Kim D;Kolte D;Kosen S;Krohn KJ;Kumar GA;Kwan GF;Lal DK;Larsson A;Linn S;Lopez A;Lotufo PA;El Razek HMA;Malekzadeh R;Mazidi M;Meier T;Meles KG;Mensah G;Meretoja A;Mezgebe H;Miller T;Mirrakhimov E;Mohammed S;Moran AE;Musa KI;Narula J;Neal B;Ngalesoni F;Nguyen G;Obermeyer CM;Owolabi M;Patton G;Pedro J;Qato D;Qorbani M;Rahimi K;Rai RK;Rawaf S;Ribeiro A;Safiri S;Salomon JA;Santos I;Santric Milicevic M;Sartorius B;Schutte A;Sepanlou S;Shaikh MA;Shin MJ;Shishehbor M;Shore H;Silva DAS;Sobngwi E;Stranges S;Swaminathan S;Tabarés-Seisdedos R;Tadele Atnafu N;Tesfay F;Thakur JS;Thrift A;Topor-Madry R;Truelsen T;Tyrovolas S;Ukwaja KN;Uthman O;Vasankari T;Vlassov V;Vollset SE;Wakayo T;Watkins D;Weintraub R;Werdecker A;Westerman R;Wiysonge CS;Wolfe C;Workicho A;Xu G;Yano Y;Yip P;Yonemoto N;Younis M;Yu C;Vos T;Naghavi M;Murray C
通讯作者：
Murray C
影响因子：
24
作者：
Maddox, Thomas M.;Januzzi, James L.;Youmans, Quentin R.
通讯作者：
Youmans, Quentin R.
影响因子：
15.9
作者：
Khalil, Hadi;Kanisicak, Onur;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.