DataSheet1_Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats.zip

Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

既往研究已证实沙库巴曲缬沙坦（sacubitril/valsartan, Sac/Val）对射血分数降低的心力衰竭（heart failure with reduced ejection fraction, HFrEF）具有临床疗效。然而，沙库巴曲缬沙坦在射血分数保留的心力衰竭（heart failure with preserved ejection fraction, HFpEF）中的作用仍不明确。沙库巴曲缬沙坦是由沙库巴曲与缬沙坦组成的复方治疗药物，属于首款血管紧张素受体脑啡肽酶抑制剂（angiotensin-receptor neprilysin inhibitor, ARNI）。本研究探讨了沙库巴曲缬沙坦在高盐饮食诱导的伴血管损伤的射血分数保留心力衰竭模型中的作用及其潜在机制。实验中，大鼠先予以高盐饲料喂养，随后予以沙库巴曲缬沙坦灌胃给药（剂量68 mg/kg；i.g.）。功能检测结果显示，高盐饮食可造成心脏与血管内皮的病理性损伤，而沙库巴曲缬沙坦治疗可显著逆转上述损伤。此外，沙库巴曲缬沙坦可显著降低包括I型胶原（type I collagen）与III型胶原（type Ⅲ collagen）在内的纤维化因子水平，同时降低基质金属蛋白酶2（matrix metalloproteinase 2, MMP2）/基质金属蛋白酶组织抑制因子2（tissue inhibitor of metalloproteinase 2, TIMP2）的比值，并上调Smad7的表达水平。进一步研究表明，沙库巴曲缬沙坦可能通过抑制转化生长因子-β1/Smad3（transforming growth factor-β1/Smad3, TGF-β1/Smad3）信号通路的激活，逆转高盐饮食诱导的射血分数保留心力衰竭表型。综上，沙库巴曲缬沙坦可有效缓解高盐饮食诱导的射血分数保留心力衰竭症状，其机制可能为通过TGF-β1/Smad3信号通路抑制心肌纤维化，这为沙库巴曲缬沙坦用于射血分数保留心力衰竭的治疗提供了潜在的应用依据。