Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy

Yi Wang,Ping Liang,Yanhong Shan,Yongmei Gao,Jin He,Zhiheng Guo

doi:10.1186/s13578-019-0348-1

Yi Wang, Ping Liang + Show 4 more

Open Access

https://doi.org/10.1186/s13578-019-0348-1

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Abstract

Pregnancy-associated cardiomyopathy (PAH) represents a pregnancy-associated myocardial disease that is characterized by the progression of heart failure due to marked left ventricular systolic dysfunction. Compelling evidence has highlighted the potential of angiotensin (Ang) receptor inhibitors as therapeutic targets in PAH treatment. The present study aims to elucidate the molecular mechanisms underlying Ang II receptor inhibitor LCZ696 treatment in PAH. Initially, a PAH mouse model was induced, followed by intraperitoneal injection of LCZ696. Subsequently, cardiomyocytes and fibroblasts were isolated, cultured, and treated with Ang II and LCZ696, followed by detection of the total survival rate, cardiac injury, cardiac fibrosis and apoptosis. Moreover, in order to quantify the cardiac hypertrophy and fibrosis degree of cardiac fibroblasts, the expression levels of markers of cardiac hypertrophy (ANP, βMHC and TIMP2) and markers of fibrosis (collagen I, collagen III and TGF-β) were evaluated. Furthermore, the potential effect of LCZ696 on the extracellular signal-regulated kinase (ERK) signaling pathway was examined. The acquired findings revealed that LCZ696 increased the total survival rate of PAH mice, but decreased cardiac injury, cardiac fibrosis, and apoptosis in vitro. LCZ696 attenuated cardiac injury induced by Ang II through the inhibition the expression of markers of cardiac hypertrophy, fibrosis and apoptosis by inhibiting ERK phosphorylation in vivo and in vitro. Altogether, LCZ676 could potentially alleviate cardiac remodeling in mice with PAH via blockade of the ERK signaling pathway activation. Our findings suggest that LCZ696 could be a potential target for PAH therapy.

Highlights

Cardiovascular diseases are predominantly known as complications that occur in the prenatal period worldwide, and there are a growing number of patients diagnosed with cardiac disorders during pregnancy [1]
The results displayed that the LCZ696 treatment improved the survival rate of pregnancy-associated cardiomyopathy (PAH) mice (Fig. 1a; p < 0.05), which suggest that LCZ696 may attenuate PAH
The results revealed that LCZ696 treatment decreased heart size and weight of PAH mice (Fig. 1b; p < 0.05)

Summary

Introduction

Cardiovascular diseases are predominantly known as complications that occur in the prenatal period worldwide, and there are a growing number of patients diagnosed with cardiac disorders during pregnancy [1]. The inhibitors of Ang II receptor may represent a promising target in the treatment of pregnancy-associated cardiomyopathy (PAH). LCZ696 is recognized as a first-class inhibitor of Ang II receptor, which can completely lessen blood pressure and even aid the treatment of hypertension and cardiovascular diseases [6]. ERK represents a mitogen activated-protein kinase (MAPK) and participates in the vascular smooth muscle cell growth which was reported to be an assuring therapeutic target for hypertension prevention [8]. This study developed a mouse PAH model through the intraperitoneal injection of LCZ696 and to determine the expected effect of LCZ696 on cardiac hypertrophy, fibrosis, and apoptosis by the regulation of the ERK signaling pathway through application of in vivo and in vitro experiments

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