Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway.
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.
Hur
Kyu Yeon
KY
Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea.
Kim
Soo Hyun
SH
Choi
Min-Ah
MA
Williams
Darren R
DR
Lee
Yong-ho
YH
Kang
Sang Won
SW
Yadav
Umesh C S
UC
Srivastava
Satish K
SK
Jung
Mankil
M
Cho
Jin Won
JW
Kim
Sang Geon
SG
Kang
Eun Seok
ES
Lee
Eun Jig
EJ
Lee
Hyun Chul
HC
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*
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