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

 Kyu Yeon Hur  ;  Soo Hyun Kim  ;  Min-Ah Choi  ;  Darren R. Williams  ;  Yong-ho Lee  ;  Sang Won Kang  ;  Umesh C.S. Yadav  ;  Satish K. Srivastava  ;  Mankil Jung  ;  Jin Won Cho  ;  Sang Geon Kim  ;  Eun Seok Kang  ;  Eun Jig Lee  ;  Hyun Chul Lee 
 ATHEROSCLEROSIS, Vol.211(1) : 69-76, 2010 
Journal Title
Issue Date
Aldehyde Reductase/metabolism ; Animals ; Antioxidants/pharmacology ; Atherosclerosis/metabolism ; Atherosclerosis/prevention & control* ; Diabetes Mellitus, Experimental/complications ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; NAD(P)H Dehydrogenase (Quinone)/physiology* ; NF-E2-Related Factor 2/physiology* ; Oxidative Stress/drug effects ; Protein Kinase C/metabolism ; Rats ; Rats, Sprague-Dawley ; Response Elements/physiology*
Diabetes mellitus ; Magnesium lithospermate B ; Nrf2 ; Oxidative stress ; Diabetic atherosclerosis
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Lee, Hyun Chul(이현철)
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