Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Abstract

Background/Aims: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. Methods: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. Results: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. Conclusions: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.

The Relationship Between Circulating Neuregulin-1 and Coronary Collateral Circulation in Patients with Coronary Artery Disease

“…13) In addition, NRG-1 has been shown to promote myocardial angiogenesis in the ischemic and diabetic myocardium and is involved in the vascular endothelial growth factor (VEGF) / Angiopoietin-1(Ang-1) angiogenesis signaling events. 11,14,15) These findings revealed that NRG-1 might participate in the development of CCC and could function as a potential biomarker. However, the association between NRG-1 and CCC has not been explored in CAD patients.…”

“…22,23) In diabetic cardiomyopathy, NRG-1 treatment can significantly promote myocardial angiogenesis and preserve cardiac function. 11) The mechanisms of the positive angiogenesis role for NRG-1 can be partly attributed to the elevated expression of VEGF and Ang-1. 11) However, another study has revealed that the expression and release of NRG-1 were significantly increased in human cardiac microvascular endothelial cells under VEGF and Ang-1 stimulation, which suggested that these angiogenic factors could regulate NRG-1 signaling pathway.…”

“…7,8) It is essential for the cardiovascular system development and repair under various stress. 9,10) Recently, increasing evidence has revealed that NRG-1 was closely related to angiogenesis 11,12) . NRG-1 can be produced by vascular endocardial and cardiac microvascular endothelium and is a positive regulator of angiogenesis.…”

Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease

“…NRG-1 induces the growth of vascular endothelial cells in vitro in a manner independent of VEGF [ 103 ]. NRG-1 treatment reverses diabetic vascular injury by increasing myocardial capillary density and increasing myocardial blood flow in mice [ 104 ]. In ischemic injury, NRG-1 treatment increases capillary density within the peri-infarct region [ 83 ].…”

“…The recent discovery of Nrp1’s dimerization of ErbB2 did not test NRGs ability to induce angiogenesis but further supports ongoing investigation into the ErbB-dependent regulation of angiogenesis. NRG-1 induces increased production and release of VEGF by endothelial cells in vivo [ 104 ]. However, in an in vivo model of corneal angiogenesis, NRG-1 induces angiogenesis independent of VEGF, suggesting that NRG is functionally angiogenic.…”