Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model

Abstract

Background: In this study, we hypothesized that the combination of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) alters the expression of connexin 43 (Cx43) and results in a reduced frequency of induced ventricular arrhythmia in rats after myocardial infarction (MI) and explored the preliminary mechanisms involved. Methods: Cardiomyocytes were cultured in vitro in medium with PBS, HGF, IGF-1, GFs (HGF + IGF-1), HGF + p38 inhibitor, HGF + ERK inhibitor, IGF-1 + p38 inhibitor or IGF-1 + ERK inhibitor. The expression of Cx43 was tested by real-time PCR and Western blotting after 48 hours. MI was induced in 48 male Sprague-Dawley rats. The rats were randomly divided into four groups and received an injection of PBS, HGF, IGF-1 or GFs into the infarct border zone two weeks after MI. Six weeks after injection, the expression levels of Cx43 and programmed stimulation-induced ventricular arrhythmias were examined. Results: In vitro, the expression of Cx43 mRNA and the Cx43 protein in cardiomyocytes was higher in the HGF, IGF-1, and GFs groups than in the PBS group. GFs had a combinatorial effect on the Cx43 mRNA level but not on the Cx43 protein level. There was a significant reduction in Cx43 mRNA and Cx43 protein levels in the IGF-1 + p38 inhibitor group and IGF-1 + ERK inhibitor group compared to the IGF-1 group. In vivo, programmed stimulation significantly decreased the frequency of ventricular arrhythmia in the GFs, HGF and IGF-1 groups, and this effect was accompanied by increased immunohistochemical staining for Cx43, myocardial Cx43 protein levels and Cx43 mRNA levels in the infarct border zone of the left ventricle compared with those in the PBS group. The combinatorial effect of GFs on Cx43 expression was only observed at the mRNA level. Conclusions: Both HGF and IGF-1 enhanced the expression of Cx43 and improved induced ventricular arrhythmia in rats with MI. Both synergistic and antagonistic effects of HGF and IGF-1 were not observed. In addition, IGF-1 may function through the MAPK/p38 and ERK1/2 signaling pathways to regulate Cx43 expression.

p38 MAPK Pathway in the Heart: New Insights in Health and Disease

“…Several processes are involved in Cx43 regulation, including synthesis/degradation, phosphorylation/dephosphorylation at different residues, and cell membrane localization [ 128 ]. Cx43 expression is increased by p38 activation induced by several stimuli [ 129 , 130 , 131 , 132 , 133 ], but p38 is also implicated in Cx43 degradation [ 134 ]. The effect of p38 activation on Cx43 expression might depend on the activating stimulus and the cell type being studied.…”

“…The effect of p38 activation on Cx43 expression might depend on the activating stimulus and the cell type being studied. In cardiomyocytes, p38 activation appears to promote an increase in Cx43 mRNA and protein expression [ 129 , 130 , 131 , 132 , 133 ]. p38 can form a complex with Cx43 [ 135 , 136 ], and its activation has been reported to promote both Cx43 phosphorylation [ 135 , 137 , 138 ] and dephosphorylation (via PP2A activity) [ 136 ].…”

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases

“…). The three-dimensional geometric coordinates of the X-ray crystal structures of HO-1 (PDB code: 1UBB) and ERK (PDB code: 6DCG), two targets reported to be associated with arrhythmia, were obtained from the Protein Data Bank (PDB) (Lee et al, 2014;Yao et al, 2019). Hits were then screened from the LGZG Library using Accelrys Discovery Studio (version 3.0; Accelrys, San Diego, CA, USA) using the CDOCKER protocol.…”

HGF Treatment Promotes Cardiac Function and Cardiac Repair: Meta-analysis of Pig Models With Myocardial Infarction

“…A variety of vascular growth factors have been studied for gene therapy aiming at ameliorating cardiac function post myocardial injury, among which hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-1) have attracted wide attention [6]. HGF, an important active factor for cell development and differentiation, could regulate the expression of cardiomyocyte speci c transcription factors and structural genes through its unique tyrosine kinase receptor c-Met [7], and then play functions such as promoting angiogenesis, regulating in ammation, inhibiting brosis, and activating tissue regeneration [8].…”