Modified bFGF targeting connective tissue growth factor in the injured microenvironment improved cardiac repair after chronic myocardial ischemia

Abstract

Myocardial infarction (MI) was a cardiovascular emergency that led to heart failure, arrhythmia, and sudden death. Basic fibroblast growth factor (bFGF) was revealed to promote angiogenesis and protect cardiomyocytes against ischemic injury. But conventional delivery of bFGF in an uncontrolled manner was inefficient and diffusive, limiting its application in MI therapy. Currently, stimuli-responsive drug delivery is emphasized in tissue regeneration. The present study constructed a CFBP-bFGF recombinant protein, which could specifically target upregulated connective tissue growth factor (CTGF) and release bFGF in ischemic myocardium. In a rat model with MI, intravenous administration of CFBP-bFGF significantly accumulated in ischemic myocardium by targeting with CTGF. The responsive release of CFBP-bFGF effectively enhanced blood vessel regeneration, decreased cardiomyocyte apoptosis, and improved cardiac function recovery. In addition, the molecular mechanism was further explored by RNA sequencing and transcriptome analysis. Besides activating the pathways and genes related to angiogenesis and cardiac protection, CFBP-bFGF also decreased the expression of fibrosis-related pathways and genes, such as TGF-β. These results demonstrated that the CTGF-responsive CFBP-bFGF was effective for targeting release that promoted the functional recovery of MI.