Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway

• Published in: Atherosclerosis Vol. 211; no. 1; pp. 69 - 76
• Main Authors: Hur, Kyu Yeon, Kim, Soo Hyun, Choi, Min-Ah, Williams, Darren R, Lee, Yong-ho, Kang, Sang Won, Yadav, Umesh C.S, Srivastava, Satish K, Jung, Mankil, Cho, Jin Won, Kim, Sang Geon, Kang, Eun Seok, Lee, Eun Jig, Lee, Hyun Chul
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.07.2010; Elsevier
• Subjects: Aldehyde Reductase - metabolism; Animals; Antioxidants - pharmacology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; Diabetic atherosclerosis; Drugs, Chinese Herbal - therapeutic use; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Magnesium lithospermate B; Male; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; NAD(P)H Dehydrogenase (Quinone) - physiology; NF-E2-Related Factor 2 - physiology; Nrf2; Oxidative stress; Oxidative Stress - drug effects; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Response Elements - physiology; Magnesium lithospermate B; Oxidative stress; Nrf2; Diabetes mellitus; Diabetic atherosclerosis; Endocrinopathy; Vascular disease; Prevention; Atherosclerosis; Cardiovascular disease; Magnesium; Inorganic element
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2010.01.035

Abstract Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) – antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.