Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats

Abstract

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.

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

“…This anti-remodelling nature of ARNI is in agreement with data from other laboratories and large clinical studies. Sacubitril/valsartan prevented myocardial fibrosis and remodelling and improved cardiac function after myocardial infarction in mice [ 28 ] and rats [ 29 , 30 ], and in streptozotocin-induced diabetic hearts in mice [ 31 ]; it reduced cardiomyocyte size in Ang II-induced cardiac hypertrophy in mice [ 32 ], attenuated LV fibrosis and dysfunction in high-salt diet-induced diastolic dysfunction in rats [ 33 ], and reduced BP and prevented stroke in stroke-prone hypertensive rats [ 34 ]. A meta-analysis of clinical studies from 2010 to 2019 revealed that ARNI exerted reverse remodelling in terms of reduced LV size and hypertrophy compared with ACE inhibitors or AT1R blockers in patients with HF with a reduced LV ejection fraction [ 35 ].…”

Angiotensin receptor‐neprilysin inhibitor attenuates cardiac hypertrophy and improves diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

“…The evaluation of the effect of LCZ696 in HFpEF with animal studies is urgently needed. Zhang et al 42 reported that LCZ696 inhibited cardiac fibrosis through the TGF‐β1/Smad3 signalling pathway, thereby effectively alleviating the symptoms of high‐salt diet‐induced HFpEF in rats. Miyoshi et al 43 reported that LCZ696 had more favourable effects on the parameters of LV diastolic function and LV fibrosis in isoproterenol‐treated rats than valsartan alone.…”

“…45,46 LCZ696 treatment markedly inhibited TGF-β expression compared to valsartan, with a lower percentage of LV fibrotic area, consistent with previous findings based on other cardiac dysfunction models. 37,38,42 Hence, LCZ696 might exert its antifibrotic and antihypertrophic effects in a TGF-β1-dependent manner.…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…In these models, concurrent oral administration of sacubitril/valsartan (68 mg/kg) with doxorubicin for 6 weeks attenuated MMP activity and highly contractile protein α-smooth muscle actin (α-SMA) expression ( Boutagy et al, 2020 ), while intragastric administration of sacubitril/valsartan (68 mg/kg/day) for 4 weeks mitigated cardiac fibrosis, associated with decreases in types I and III collagen protein and mRNA expressions, as well as MMP-2 protein expression ( Zhang et al, 2021a ). Tissue inhibitor of metalloproteinase-2 (TIMP-2) and Smad7 expression—an inhibitory regulator of TGF-β ( Ma et al, 2018 )—were increased in the rats ( Zhang et al, 2021a ), suggestive of a strong suppressive effect of the drug on myocardial fibrosis production.…”