Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction

ABSTRACT: Background. Accumulation of extracellular matrix in the myocardium attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Connective tissue growth factor (CTGF) is a matricellular protein that has been shown to promote development of cardiac fibrosis. Objectives. To investigate for the potential of CTGF monoclonal antibody (CTGF mAb) in protecting from development of cardiac fibrosis following myocardial infarction (MI), and to evaluate its effect during infarct repair and acute cardiac ischemia-reperfusion (I/R) injury. Methods. Mice were subjected to MI or to I/R injury and treated with either control IgG or CTGF mAb. Cultured human cardiac fibroblasts were used to investigate the signalling mechanisms modulated by CTGF mAb. Results. Treatment with CTGF mAb for four days from day three after MI improved survival, attenuated infarct expansion, and resulted in better preserved left ventricular (LV) systolic function. CTGF mAb therapy for six weeks from day seven after MI reduced the MI-induced increase in cardiomyocyte size, heart weight to body weight ratio and remote LV fibrosis. RNA sequencing analysis of LV samples showed that CTGF mAb induced expression of cardiac repair/developmental genes and normalized the MI-induced increase in expression of inflammatory/profibrotic genes. CTGF mAb induced c-Jun N-terminal kinase (JNK) phosphorylation in vivo and in vitro, and inhibition of JNK abrogated the reduced collagen production in CTGF mAb treated fibroblasts. Conclusions. Treatment with CTGF mAb induces expression of cardiac repair/developmental genes and inhibits expression of inflammatory/pro-fibrotic genes in MI hearts providing benefit during post-MI cardiac repair and reducing post-MI cardiac fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE129134 | GEO | 2019/04/02

REPOSITORIES: GEO