Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α.

Yufei Zhou,Kai Wang,Mengsha Shi,Mengli Chen,Xinli Li,Yanxiu Li,Xiaodong Wu,Hongcai Shang,Ting Yin,Iokfai Cheang,Haifeng Zhang,Nanping Wang

doi:10.1155/2021/9947656

Abstract

Materials and Methods C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson's trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. Results Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Conclusions Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.

Highlights

Chronic heart failure (CHF) is associated with high morbidity and mortality worldwide [1]
As shown by echocardiography, compared with the sham group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly decreased in the Myocardial infarction (MI) group, and the left ventricular internal diameter at end diastole (LVIDd) and left ventricular internal diameter at end systole (LVIDs) were enlarged
The heart weight/body weight ratio increased in the MI group compared with that in the NOB intervention group, confirming that decompensated hypertrophy was alleviated after NOB intervention (Figure 1(e))

Summary

Introduction

Chronic heart failure (CHF) is associated with high morbidity and mortality worldwide [1]. Myocardial infarction (MI) is the most prominent cause of CHF [2]. Pathological cardiac remodeling following MI represents a pivotal mechanism that underlies CHF development and involves three predominant pathways [4]. The cell loss pathway is associated with cardiomyocyte necrosis and apoptosis, the decompensated cardiac hypertrophy pathway is induced by abnormal oxidative stress and energy metabolism, and the fibrosis pathway is manifested by the activation of myofibroblasts and monocyte infiltration [5]. Due to the limited regenerative abilities of cardiomyocytes, cardiac infarcts often result in the development of scar tissue, which can contribute to pathological cardiac remodeling [6, 7]. The mechanisms underlying cardiac remodeling are well understood, few therapeutic targets exist to alleviate the pathological cardiac remodeling that occurs after MI; the identification of novel targets remains an urgent goal

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Discussion

Conclusion