CD47 Deficiency Attenuates Isoproterenol-Induced Cardiac Remodeling in Mice.

Zhi Zuo,Ming-Yue Ji,Kun Zhao,Yong Li,Dao-Rong Hou,Zhong-Ping Su,Peng Li

doi:10.1155/2019/7121763

Abstract

In this study, we investigated whether CD47 deficiency attenuates isoproterenol- (ISO-) induced cardiac remodeling in mice. Cardiac remodeling was induced by intraperitoneal (i.p.) injection of ISO (60 mg·kg−1·d−1 in 100 μl of sterile normal saline) daily for 14 days and was confirmed by increased levels of lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB), increased heart weight to body weight (HW/BW) ratios, and visible cardiac fibrosis. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were found to be significantly higher in the ISO group than in the control group, while superoxide dismutase (SOD) levels were suppressed in the ISO group. However, CD47 knockout significantly limited ISO-induced increases in LDH, CK-MB, and HW/BW ratios, cardiac fibrosis, oxidative stress, and apoptosis in the heart. In addition, CD47 deficiency also increased p-AMPK and LAMP2 expression and decreased HDAC3, cleaved Caspase-3, cleaved Caspase-9, LC3II, and p62 expression in cardiac tissues. In conclusion, CD47 deficiency reduced i.p. ISO-induced cardiac remodeling probably by inhibiting the HDAC3 pathway, improving AMPK signaling and autophagy flux, and rescuing autophagic clearance.

Highlights

Cardiac remodeling is a major cause of morbidity and mortality worldwide [1]
Cardiac hypertrophy is a common compensatory response of the heart to acute myocardial injury, infection, or hemodynamic stress [49]. β-Adrenergic agonists enhance cardiomyocyte proliferation and hypertrophy and promote cardiac fibroblast proliferation and cardiac dysfunction [50], all of which contribute to cardiac remodeling
Cytosolic enzymes such as creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH), which serve as diagnostic markers, leak from the damaged tissue into the blood stream when the cell membrane becomes permeable or ruptures [52]

Summary

Introduction

Cardiac remodeling is a major cause of morbidity and mortality worldwide [1]. As patients with major remodeling undergo progressive worsening of cardiac function, slowing or preventing cardiac remodeling has become a new goal of heart failure therapy [9, 10]. Β-Adrenergic receptors, or β-adrenoceptors (β-ARs), play important roles in the regulation of cardiac excitation contraction and are essential regulators of cardiovascular homeostasis [11]; overactivation of β-adrenergic signaling can lead to cardiac remodeling [12, 13]. Treatment with isoproterenol (ISO), a nonselective agonist of β-ARs, has been widely used to induce cardiac hypertrophy and subsequent heart failure in experimental animals [14,15,16]. ISO is the main agent used to induce cardiac hypertrophy models because it is convenient and yields rapid and reproducible

Methods

Results

Conclusion