Gene transfer of human neuregulin-1 attenuates ventricular remodeling in diabetic cardiomyopathy rats

Abstract

Neuregulin-1 (NRG-1) is a cardioactive growth factor released from endothelial cells. However, the effect of NRG-1 on ventricular remodeling in diabetic cardiomyopathy (DCM) remains unclear. The aim of the present study was to investigate the pathophysiological role of NRG-1 in a rat model of DCM. Rat cardiac microvascular endothelial cells (CMECs) were transfected with human NRG-1 (hNRG-1) lentivirus. The hNRG-1 medium was utilized to culture rat cardiomyocytes. The cardiomyocytes were counted with a hemacytometer to determine the proliferation index and Annexin V/propidium iodide double staining was employed to examine the apoptotic rate. A rat model of DCM was induced by an intraperitoneal injection of streptozotocin. The hNRG-1 lentivirus was injected into the myocardium of the DCM model rats. Four weeks after the lentiviral injection, cardiac catheterization was performed to evaluate the cardiac function. Apoptotic cells were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Left ventricular sections were stained with Masson’s trichrome to investigate the myocardial collagen content. The expression levels of related genes and proteins were analyzed. The results indicated that hNRG-1 conditioned medium stimulated the proliferation and counteracted the apoptosis of cardiomyocytes in vitro. In the rats with DCM, gene transfer of hNRG-1 to the myocardium improved heart function, as indicated by invasive hemodynamic measurements. In addition, hNRG-1 reduced the number of apoptotic cells, decreased the expression of bax and increased the expression of bcl-2 in the myocardium of the DCM model rats. Myocardial fibrosis and type I and III pro-collagen mRNA levels in the myocardium were significantly reduced by hNRG-1. hNRG-1 also increased the expression of phospho-Akt and phospho-eNOS in the myocardium. In conclusion, the gene transfer of hNRG-1 ameliorates cardiac dysfunction in diabetes. Although further studies are required, NRG-1 appears to protect cardiomyocytes against apoptosis and to reduce the extent of myocardial interstitial fibrosis.

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

“…In a chronic stabilized condition, NRG-1 may induce cardiomyocyte mitosis and promote myocardial regeneration (3). Also, protection against diabetic cardiomyopathy in type 1 diabetes has been described (22,23). Consistent with previous data, rhNRG-1 reversed cardiac MHC␣ downregulation and enhanced LV eNOS phosphorylation, presumably contributing to improved contractile function and reduced LV remodeling (22,24).…”

“…Consistent with previous observations, phosphorylation of LV eNOS in rhNRG-1-treated mice was enhanced, both in apoE Ϫ/Ϫ control and in apoE Ϫ/Ϫ STZ mice ( Fig. 1D) (22).…”

“…In animals, recombinant NRG-1 has beneficial effects on several forms of cardiomyopathy, including ischemic, toxic, viral, and diabetic cardiomyopathy (23,26). With specific relation to diabetes, endogenous NRG-1 signaling may be impaired in type 1 diabetic cardiomyopathy, while exogenous treatment with NRG-1 has reversed cardiac remodeling in diabetic rats (14,22,23,34). Currently, two forms of recombinant NRG-1 are being examined in clinical trials as potential therapies for heart failure with a reduced left ventricular (LV) ejection fraction (12,17).…”

Expression and secretion of neuregulin-1 in cardiac microvascular endothelial cells treated with angiogenic factors

“…So these findings indicate HCMECs and SMC can participate in both autocrine and paracrine regulation via NRG-1/ErbB signaling, an important potential mechanism for regulation of vascular responses. ErbB2 and ErbB4 are expressed in cardiomyocytes, the crosstalk between endothelial cells and cardiomyocytes via this pathway can have profound effects on myocardial function and survival (23).…”

Exogenous neuregulin-1 attenuates STZ-induced diabetic peripheral neuropathic pain in rats

“…Till now, NRG1 is the most extensively characterized of the NRGs family, which has a key role in neural and cardiac development. NRG1 can not only modulate synaptic plasticity, but also stimulate the proliferation, survival and motility of a number of different cell types through binding to ErbB tyrosine kinase [2][3][4] . It has also shown that NRG1 is required for the development of the peripheral nervous system.…”