Antifibrotic Effect of a Novel Selective 11β-HSD2 Inhibitor (WZ51) in a rat Model of Myocardial Fibrosis.

Fei Zhuang,Xiaodan Zhang,Qin Ge,Mengchun Chen,Jianchang Qian,Yaoyao Dong,Wei Sun,Zhe Wang

doi:10.3389/fphar.2021.629818

Abstract

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.

Highlights

Cardiovascular diseases, such as hypertension and myocardial infarction, are the leading cause of death worldwide (Sorriento and Iaccarino, 2019)
An important pathological feature of cardiovascular disease is Myocardial fibrosis (MF), which can lead to ventricular remodeling (Hughes et al, 2019)
MF is the abnormal deposition of extracellular matrix in the myocardium, which is characterized by increased collagen deposition in the interstitium, and an imbalanced and disordered collagen ratio (Essick and Sam, 2011)

Summary

Introduction

Cardiovascular diseases, such as hypertension and myocardial infarction, are the leading cause of death worldwide (Sorriento and Iaccarino, 2019). Myocardial fibrosis (MF) can lead to myocardial remodeling, making it an important pathological feature of heart failure (Gulati et al, 2018; Kong et al, 2020). Slowing down the development of MF is an optimized strategy for reducing the risk of death from cardiovascular disease. Myocardial hypertrophy, perivascular fibrosis, and myocardial interstitial fibrosis can be caused by aldosterone via the MR. MR antagonists are the main drugs used for the clinical treatment of MF (Milliez et al, 2005). MR antagonists can cause adverse drug reactions such as hyperkalemia, gynecomastia, and erectile dysfunction in patients (Grune et al, 2016; Young and Adler, 2019; Khan et al, 2020)

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Conclusion