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 Srivastava, Mankil Jung, Jin Won Cho, Sang Geon Kim, Eun Seok Kang, Eun Jig Lee, Hyun Chul Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalAtherosclerosis
Volume211
Issue number1
DOIs
StatePublished - Jul 2010

Fingerprint

NAD
Atherosclerosis
Oxidoreductases
Antioxidants
Vascular Smooth Muscle
Smooth Muscle Myocytes
Oxidative Stress
lithospermate B
benzoquinone
Aldehyde Reductase
Diabetes Complications
Carotid Arteries
Hyperglycemia
Protein Kinase C
Small Interfering RNA
Hyperplasia
Blood Vessels
Catheters
Cell Culture Techniques
Glucose

Keywords

  • Diabetes mellitus
  • Diabetic atherosclerosis
  • Magnesium lithospermate B
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. / Hur, Kyu Yeon; Kim, Soo Hyun; Choi, Min Ah; Williams, Darren R.; Lee, Yong ho; Kang, Sang Won; Yadav, Umesh C S; Srivastava, Satish; Jung, Mankil; Cho, Jin Won; Kim, Sang Geon; Kang, Eun Seok; Lee, Eun Jig; Lee, Hyun Chul.

In: Atherosclerosis, Vol. 211, No. 1, 07.2010, p. 69-76.

Research output: Contribution to journalArticle

Hur, KY, Kim, SH, Choi, MA, Williams, DR, Lee, YH, Kang, SW, Yadav, UCS, Srivastava, S, Jung, M, Cho, JW, Kim, SG, Kang, ES, Lee, EJ & Lee, HC 2010, 'Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway', Atherosclerosis, vol. 211, no. 1, pp. 69-76. https://doi.org/10.1016/j.atherosclerosis.2010.01.035
Hur, Kyu Yeon ; Kim, Soo Hyun ; Choi, Min Ah ; Williams, Darren R. ; Lee, Yong ho ; Kang, Sang Won ; Yadav, Umesh C S ; Srivastava, Satish ; Jung, Mankil ; Cho, Jin Won ; Kim, Sang Geon ; Kang, Eun Seok ; Lee, Eun Jig ; Lee, Hyun Chul. / Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. In: Atherosclerosis. 2010 ; Vol. 211, No. 1. pp. 69-76.
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AU - Williams, Darren R.

AU - Lee, Yong ho

AU - Kang, Sang Won

AU - Yadav, Umesh C S

AU - Srivastava, Satish

AU - Jung, Mankil

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AU - Kim, Sang Geon

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AU - Lee, Eun Jig

AU - Lee, Hyun Chul

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N2 - 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.

AB - 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.

KW - Diabetes mellitus

KW - Diabetic atherosclerosis

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KW - Nrf2

KW - Oxidative stress

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