Sacubitril/Valsartan Inhibits Cardiomyocyte Hypertrophy in Angiotensin II-Induced Hypertensive Mice Independent of a Blood Pressure-Lowering Effect

Abstract

Background: Hypertensive left ventricular hypertrophy is associated with the risk of heart failure, coronary heart disease and cerebrovascular disease. Although sacubitril/valsartan (SAC/VAL), a first-in-class angiotensin receptor neprilysin inhibitor, reduces the risks of death and hospitalization for patients with heart failure, its mechanism of action is not fully understood. We hypothesized that SAC/VAL is superior to other conventional drugs in reducing cardiac hypertrophy.Methods: Male C57BL/6J mice were implanted with an osmotic pump containing angiotensin II (Ang II). After 7 days of Ang II infusion, mice were also treated with either SAC/VAL, valsartan, enalapril or vehicle alone each day for 2 weeks. Blood pressure measurement was done weekly, and echocardiography was performed before and 3 weeks after infusion of Ang II. Histological analyses were done using extracted heart to investigate cardiac hypertrophy and fibrosis.Results: Ang II markedly elevated blood pressures in all of the treatment groups, and there were no differences in the degree of blood pressure reduction among the SAC/VAL-, valsartan-and enalapriltreated groups. Echocardiography showed that SAC/VAL significantly suppressed the increase in left ventricular (LV) wall thickness and tended to decrease LV mass. In a histological analysis, SAC/VAL inhibited Ang II-induced cardiomyocyte hypertrophy, and individual cardiomyocytes in the SAC/VAL group were smaller than those in the valsartan and enalapril groups. Although previous studies using animal models of heart failure have indicated that SAC/VAL attenuates cardiac fibrosis, we found no supporting evidence in this setting.Conclusions: SAC/VAL, valsartan and enalapril all attenuated cardiomyocyte hypertrophy in a mouse model of Ang II-induced cardiac hypertrophy. Of note, SAC/VAL most strongly suppressed hypertrophy in spite of similar blood pressure-lowering effects as valsartan and enalapril. The present study suggests that SAC/VAL may have a beneficial effect on the early stage of hypertensive heart disease.

An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

“…Similarly, TGF-β has been proposed to act in a paracrine/ autocrine manner between fibroblast and cardiomyocytes to stimulate cardiac remodeling (Leask, 2010). Valsartan, angiotensin receptor blocker, or Stachydrine mediated inhibition of Ang II/AT1 R/TGF-β signaling is a pivotal mechanism of anti-hypertrophic and anti-fibrotic effect (Teekakirikul et al, 2010;Liu et al, 2019;Tashiro et al, 2020). Ang II-induced fibrosis is associated with altered expression of inflammation-related genes such as TGF-β, TNF-α, MCP-1, IL-6, and type 3 collagen (Azushima et al, 2019).…”

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 ].…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…It inhibited left ventricular hypertrophy in various models of cardiac hypertrophy, which was confirmed echocardiographically and histologically. Echocardiographic analysis revealed that sacubitril/valsartan decreased left ventricular wall thickness as shown by decreased interventricular septum thickness diameter, left ventricular posterior diastolic wall thickness, left ventricular mass, and left ventricular end-systolic diameter ( Chang et al, 2019 ; Zhao et al, 2019 ; Tashiro et al, 2020 ), leading to improved cardiac geometry ( Sung et al, 2020 ). Meanwhile, histological analysis showed that the increases in cardiomyocyte size induced by Ang II was significantly attenuated by the treatment ( Tashiro et al, 2020 ).…”

“…Echocardiographic analysis revealed that sacubitril/valsartan decreased left ventricular wall thickness as shown by decreased interventricular septum thickness diameter, left ventricular posterior diastolic wall thickness, left ventricular mass, and left ventricular end-systolic diameter ( Chang et al, 2019 ; Zhao et al, 2019 ; Tashiro et al, 2020 ), leading to improved cardiac geometry ( Sung et al, 2020 ). Meanwhile, histological analysis showed that the increases in cardiomyocyte size induced by Ang II was significantly attenuated by the treatment ( Tashiro et al, 2020 ). However, a detailed molecular mechanism of sacubitril/valsartan inhibition on left ventricular hypertrophy was not fully characterized.…”

“…However, studies have indicated that the antihypertrophic effects of sacubitril/valsartan were independent of blood pressure. Tashiro et al (2020) exhibited that the fewest hypertrophic changes—interventricular septum thickness diameter, left ventricular posterior wall thickness diameter and cardiomyocyte cross-sectional area—took place in the sacubutril/valsartan-treated mice treated with Ang II, despite the similar blood pressure-lowering effect of sacubitril/valsartan, enalapril, and valsartan ( Tashiro et al, 2020 ). A similar finding was also noted in a rat model of heart failure with preserved ejection fraction (HFpEF) ( Nordén et al, 2021 ).…”