Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2}

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2}
http://www.vascularpath.org/projects.htm

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Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane bound NADPH oxidases (NOX). The NADPH oxidases generate superoxide in the extracellular space that both inactivates nitric oxide and is dismutated into hydrogen peroxide by extracellular superoxide dismutase (ECSOD).

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(Memo Item created on January 15, 2009 02:33 PM)
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Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S.

http://www.vascularpath.org/projects.htm
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Home | Projects | Lab Members | Publications | Links | Biographical Sketch | Contact

Projects

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. The laboratory is seeking to understand the biochemical processes resulting in atherosclerosis in order to combat this pervasive disease.

Atherosclerosis is characterized by the development of necrotic/lipid cores within the intima of arteries at particular sites in the circulation. These necrotic/lipid cores form in the setting of a pre-existing intimal hyperplasia, characterized by the proliferation of smooth muscle-like cells within the intima. The laboratory is investigating both the mechanisms of signal transduction responsible for the formation of the pre-atherosclerotic intimal hyperplasia, as well as the factors stimulating the formation of intimal necrotic/lipid cores. Signal Transduction with Hydrogen Peroxide in Vascular Cells

Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane bound NADPH oxidases (NOX). The NADPH oxidases generate superoxide in the extracellular space that both inactivates nitric oxide and is dismutated into hydrogen peroxide by extracellular superoxide dismutase (ECSOD). These low physiologic levels of hydrogen peroxide are mitogenic, stimulating vascular cell growth and proliferation.

The mechanisms by which low endogenous levels of hydrogen peroxide stimulate cellular proliferation are currently poorly understood. The laboratory is using proteomic approaches with cultured vascular cells to identify signal transduction pathways activated by low physiologic levels of hydrogen peroxide. One target protein identified is the nuclear pre-mRNA binding protein hnRNP-C. Low physiologic levels of hydrogen peroxide stimulate the hyperphosphorylation of the acidic C-terminal domain of hnRNP-C, resulting in diminished ability of the protein to bind mRNA. The effect is mediate by protein kinase CK1 Other groups have previously shown that hnRNP-C is hyperphosphorylated during mitosis, and that CK1 entry into the nucleus is required for cell cycle progression. Proteomic Analyses of Intimal Hyperplasia from Atherosclerosis-Prone and Atherosclerosis-Resistant Human Arteries

Pre-atherosclerotic intimal hyperplasia forms at branch sites both in arteries prone to develop atherosclerosis, such as the internal carotid and coronary arteries and also in vessels remarkably resistant to the formation of atherosclerosis, such as the internal thoracic artery and the distal ulnar artery. The structural variations in intimal hyperplasia that may facilitate the development of atherosclerosis have been unclear. Proteoglycans have been implicated as playing a direct role in atherosclerosis, both by binding and retaining lipoproteins in the vessel wall and by regulating cell growth. One project in the laboratory has been to analyze by mass spectrometry the extracellular proteoglycans present in pre-atherosclerotic intimal hyperplasia from atherosclerosis-prone arteries as well as atherosclerosis-resistant arteries. This project has revealed the proteoglycan composition of human intimal hyperplasia to be more complex than previously realized with eight distinct proteoglycans present: perlecan, versican, aggrecan, biglycan, decorin, fibromodulin, lumican, and prolargin. Importantly, while most of the proteoglycans are present at similar levels in the two arterial types, there is a selective enhanced deposition of lumican proteoglycan in the pre-atherosclerotic intimal hyperplasia from the atherosclerosis-prone artery compared with the intimal hyperplasia from the atherosclerosis-resistant artery. This data suggests that lumican may play a central role in the development of atherosclerotic lesions in humans, and may partly account for site-specific susceptibility to atherosclerosis. Home | Projects | Lab Members | Publications | Links | Biographical Sketch | Contact

Massachusetts General Hospital | Simches Building, Rm 8236
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©2007 James R. Stone Lab - Department of Pathology - Massachusetts General Hospital

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2009-03-17
File Index: 0001
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Keywords:
Hydrogen peroxide, increased, glutathione (GSH), L-Cysteine, Atherosclerosis (【醫學】動脈粥狀硬化), cardiovascular (【醫學】心血管性的), stroke (中風)

Number of attached files: 
3