Zhang Wenchao, Liu Jianwei, Fu Yang, Ji Huifang, Fang Zheyan, Zhou Wanming, Fan Huimin, Zhang Yingxuan, Liao Yan, Yang Ting, Wang Xiaolin, Yuan Wanwan, Chen Xiaoshu, Dong Yi-Fei
Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
Chang Xing People's Hospital, Huzhou, China.
Front Pharmacol. 2021 Jan 14;11:600953. doi: 10.3389/fphar.2020.600953. eCollection 2020.
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.
先前的研究已经证实了沙库巴曲缬沙坦（Sac/Val）治疗射血分数降低的心力衰竭（HFrEF）的临床疗效。然而，Sac/Val在射血分数保留的心力衰竭（HFpEF）中的作用仍不清楚。Sac/Val是一种由沙库巴曲和缬沙坦组成的复方治疗药物，作为首个血管紧张素受体阻滞剂和中性肽链内切酶抑制剂（血管紧张素受体脑啡肽酶抑制剂（ARNI））。在此，我们研究了Sac/Val在高盐饮食诱导的HFpEF合并血管损伤中的作用及其潜在机制。给大鼠喂食高盐饲料，随后灌胃给予Sac/Val（68mg/kg；腹腔注射）。功能测试结果显示，高盐饮食导致心脏和血管内皮出现病理损伤，而Sac/Val治疗可显著逆转这些损伤。此外，Sac/Val显著降低了包括I型胶原和III型胶原在内的纤维化因子水平，从而降低了MMP2/TIMP2的比值，同时提高了Smad7水平。进一步研究表明，Sac/Val可能通过抑制TGF-β1/Smad3信号通路的激活来逆转高盐饮食诱导的HFpEF的影响。因此，Sac/Val治疗有效缓解了高盐饮食诱导的HFpEF症状，可能是通过TGF-β1/Smad3信号通路抑制纤维化，这支持了Sac/Val治疗HFpEF的潜在治疗价值。
