Abstract
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.
Highlights
Cardiovascular disease, especially ischemic heart disease, remains the leading cause of death around the world, accounting for 30% of all-cause deaths (Roth et al, 2017)
Sacubitril/valsartan treatment reversed the above adverse change of cardiac structure and function induced by myocardial infarction, and this effect was superior to the traditional heart failure drugs valsartan, which was characterized by a further significant improvement in left ventricular end-systolic dimension (LVEDs), left ventricular posterior wall thickness in diastole (LVPWd), left ventricular ejection fraction (LVEF), and fractional shortening (FS) (p < 0.05), and a non-significant decrease trend in left ventricular end-diastolic dimension (LVEDd) and IVSd (p > 0.05) (Figure 1)
Small bundles of diffuse red-stained fibers were observed in the infarcted myocardium of rats receiving valsartan treatment, while only fine bundles of redstained fibers were observed in the infarcted myocardium of rats receiving sacubitril/valsartan treatment (Figure 2A)
Summary
Cardiovascular disease, especially ischemic heart disease, remains the leading cause of death around the world, accounting for 30% of all-cause deaths (Roth et al, 2017). Early reperfusion therapy for acute myocardial infarction (MI) can effectively salvage ischemic myocardium, a considerable portion of cardiomyocytes may still occur irreversible necrosis and loss, followed by ventricular remodeling and cardiac insufficiency, which compromises the long-term survival of patients with myocardial infarction. In the landmark clinical trial of PARADIGM-HF, sacubitril/valsartan was demonstrated to outperform angiotensin-converting enzyme inhibitor (ACEI) in reducing heart failure hospitalization and cardiovascular death (McMurray et al, 2014). Sacubitril/ valsartan has been consistently recommended by national guidelines as a preferred treatment for heart failure with reduced ejection fraction to further reduce mortality and heart failure hospitalization when patients were still symptomatic after giving ACEI or ARB treatment (Ponikowski et al, 2016; Yancy et al, 2016; Maddox et al, 2021). There is scarce data regarding the effect and mechanism of sacubitril/valsartan in the setting of acute myocardial infarction (von Lueder et al, 2015; Ishii et al, 2017; Torrado et al, 2018)
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