title: Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway.
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.
authors.affiliation: Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Min-Ah
authors.initials: MA
authors.lastname: Choi
authors.forename: Darren R
authors.initials: DR
authors.lastname: Williams
authors.forename: Yong-ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Umesh C S
authors.initials: UC
authors.lastname: Yadav
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Mankil
authors.initials: M
authors.lastname: Jung
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Cho
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000502:physiology*
chemical_list: D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C061091:lithospermate B; D000449:Aldehyde Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D011493:Protein Kinase C