CTRP1 Aggravates Cardiac Dysfunction Post Myocardial Infarction by Modulating TLR4 in Macrophages.

Pei-Bing Ge,Xi-Wen Zhang,Yu Chen,Xiao Hu,Shen Wu,Yang Gu

doi:10.3389/fimmu.2021.635267

Abstract

CTRP1 (C1q/TNF-α [tumour necrosis factor-α]-related protein 1), an adiponectin paralog, is associated with diabetes and adverse events in cardiovascular disease. However, its effect on cardiac function post myocardial infarction (MI) is unclear. Our study aimed to explore the role of CTRP1 in cardiac function post MI. CTRP1 global knockout mice were subjected to left anterior descending ligation to establish the MI model. C57BL6J mice were also administered recombinant CTRP1 protein (200 μg/kg) 7 days post MI. As a result, mice with CTRP1 deficiency exhibited an increased survival rate, a reduced infarct area, improved cardiac function and decreased inflammation and oxidative stress levels at 4 weeks post MI compared with those of mice receiving the CRTP1 injection, whose conditions deteriorated. However, cardiomyocytes with either CTRP1 silencing or CTRP1 treatment showed few differences in inflammation and oxidative stress levels compared with those of the control under hypoxic conditions. The activation of macrophages isolated from CTRP1-deficient mice was decreased in response to interferon-γ, while CTRP1 enhanced the activation of macrophages in response to interferon-γ. Macrophage scavengers and clodronate liposomes antagonized the effects of CTRP1 injection in mice. We also found that CTRP1 regulated macrophage activation via adiponectin receptor 1, which binds to TLR4 on the macrophage membrane. TLR4 knockout also antagonized the effects of the CTRP1 protein on mice with MI. Taken together, these data indicate that CTRP1 supresses cardiac function post MI via TLR4 on macrophages. Targeting CTRP1 may become a promising therapeutic approach to cardiac dysfunction post MI.

Highlights

During the acute phase of myocardial infarction (MI), cardiomyocyte necrosis leads to the initiation of the inflammatory response [1]
CTRP1 in heart tissue was sharply elevated in MI group (Figure 1C)
We found the following: 1) CTRP1 was upregulated in both mouse hearts and heart macrophages after MI. 2) CTRP1 negatively affected the cardiac remodelling process post MI, and CTRP1 deficiency improved cardiac dysfunction, inflammation, and OS post MI. 3) CTRP1 did not affect cardiomyocytes under hypoxic conditions but rather affected the functionality of macrophages, which was consistent with the inflammation and OS in cardiomyocytes

Summary

Introduction

During the acute phase of myocardial infarction (MI), cardiomyocyte necrosis leads to the initiation of the inflammatory response [1]. Damage-associated molecular patterns (DAMPs) from necrotic cardiomyocytes bonded to specific pattern recognition receptors (PRRs) on the surface of inflammatory cells and other surviving cardiomyocytes cause an inflammatory cascade [3]. This inflammation is beneficial in the early stage of MI, as it accelerates the clearance of dead cardiomyocytes and promotes cardiac. During the late stage (more than 14 days post MI), sustained inflammation and fibrosis cause cardiac remodelling and heart failure [5]. Many PRRs, such as Toll-like receptor (TRL) and NOD-like receptor (NLR) family members, account for the persistence of inflammation [6, 7], and targeting these receptors may be a promising therapeutic strategy for cardiac remodelling post MI

Methods

Results

Conclusion