Improvement of cardiac dysfunction by L-arginine combined with vitamin C through restoring angiogenesis associated with NADPH/NOS/NO signal pathway in diabetic rats

Abstract

Background In diabetic patients, the occurrence of ischemic events such as myocardial infarction is significantly higher than that of normal patients. L-arginine and vitamin C are commonly used adjuvant drugs in clinical practice. But whether L-arginine and vitamin C can be used together, the role of promoting angiogenesis to improve vascular dysfunction and its mechanism of action are not clear. To this end, we investigated whether L-arginine in combination with vitamin C promotes revascularization after myocardial infarction in patients with type 2 diabetes by inhibiting angiogenesis disorders associated with NADPH oxidase. Methods Experimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in diabetic Sprague-Dawley rats and non-diabetic controls. Cardiac function was studied by echocardiography and LDH activity. Western blotting was used to study VEGF, Nox4, Nox1, Nox2, eNOS and phospho-eNOS (Ser1177), CAT-1. Angiogenesis, cell proliferation and migration were detected by micro-vessel density assay, cell viability assay, scratch wound-healing assay and tube formation assay. Results First, we cultured rat aortic endothelial cells in a high glucose environment for 48 hours, then treated L-arginine and vitamin C alone or together. It was shown that high glucose significantly damaged cell proliferation, migration and tube formation, which was normalized by L-arginine with vitamin C combined application. Furthermore, we found that co-treatment of L-arginine and vitamin C activated NOS/NO signaling pathway via inhibited NADPH oxidase activity, which regulated angiogenesis in RAECs. In vivo, L-arginine and vitamin C co-intervention improved cardiac function by implementing echocardiographic examination and LDH activity. This therapy also relieved the vasodilatory response to acetylcholine and restored the expressions of p-eNOS and VEGF, together with reducing Nox2 and iNOS production in the ischemic myocardium of high-fat diet (HFD)-fed rats following streptozocin (STZ) injection. Conclusion Overall, for the first time, this study reveals that the combination of L-arginine and vitamin C restores the blood supply to myocardial infarction in rats with type 2 diabetes by promoting angiogenesis, which was attributed to activating NOS/NO signaling pathway via blocking NADPH-dependent O2− generation.