Therapeutic effects of neuregulin-1 in diabetic cardiomyopathy rats

Abstract

BackgroundDiabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes, which is characterized by both systolic and diastolic dysfunction. The effective treatment strategy for DCM has not been developed.MethodsRats were divided into 3 groups with different treatment. The control group was only injected with citrate buffer (n = 8). The diabetes group and diabetes treated group were injected with streptozotocin to induce diabetes. After success of diabetes induction, the rats with diabetes were treated with (diabetes treated group, n = 8) or without (diabetes group, n = 8) recombinant human Neuregulin-1 (rhNRG-1). All studies were carried out 16 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate the cardiac function. Apoptotic cells were determined by TUNEL staining. Left ventricular (LV) sections were stained with Masson to investigate myocardial collagen contents. Related gene expressions were analyzed by quantitative real-time PCR (qRT-PCR).ResultsDiabetes impaired cardiac function manifested by reduced LV systolic pressure (LVSP), maximum rate of LV pressure rise and fall (+dp/dt max and -dp/dt max) and increased LV end-diastolic pressure (LVEDP). The rhNRG-1 treatment could significantly alleviate these symptoms and improve heart function. More TUNEL staining positive cells were observed in the diabetic group than that in the control group, and the rhNRG-1 treatment decreased apoptotic cells number. Furthermore, qRT-PCR assay demonstrated that rhNRG-1 treatment could decrease the expression of bax and caspase-3 and increase that of bcl-2. Collagen volume fraction was higher in the diabetic group than in the control group. Fibrotic and fibrotic related mRNA (type I and type III collagen) levels in the myocardium were significantly reduced by administration of rhNRG-1.ConclusionrhNRG-1 could significantly improve the heart function and reverse the cardiac remodeling of DCM rats with chronic heart failure. These results support the clinical possibility of applying rhNRG-1 as an optional therapeutic strategy for DCM treatment in the future.

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

“…These observations may be different from previous studies with rhNRG-1 in diabetic models (22,23). In this study, absence of increased myocardial fibrosis was confirmed by three immunohistological staining methods and by mRNA analysis of fibrotic markers.…”

“…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).…”

“…In postnatal life, NRG-1 released by cardiac endothelial cells has cell-protective, regenerative, and antifibrotic effects in the myocardium (3,11). 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).…”

“…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).…”

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

“…The ErbB4 agonist neuregulin1 (NRG1) rescues adult ventricular myocytes from hypoxia-reoxygenation-induced apoptosis, whereas the endothelium-selective deletion of NRG1 decreases the ability of the myocytes to tolerate an ischemic insult (Hedhli et al, 2011). Exogenous NRG1 also decreased the number of apoptotic cells and improved heart function in a rat model of diabetic cardiomyopathy with systolic and diastolic dysfunction (Li et al, 2011), and in cultured myocytes NRG1 inhibits the apoptosis induced by serum starvation (Zhao et al, 1998). Taken together, these studies indicate that NRG-ErbB4 signalling is important in cardiac protection.…”