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Richard Cohen, M.D.

The Cell Biology of the Diseased Vessel Wall

The Vascular Biology Unit led by Dr. Richard Cohen seeks to understand why oxidants impair function of diseased arteries. His group has found that in diabetes, hypertension, and atherosclerosis, the vasodilator, nitric oxide is inactivated by superoxide, an oxidant produced in diseased blood vessels. As a result of this reaction an even more potent oxidant, peroxynitrite, is formed. At low levels, peroxynitrite S-glutathiolates proteins including the sarcoplasmic reticulum calcium ATPase and p21ras, modulating cell signaling. High levels of peroxynitrite can be blamed for inactivating these and other important proteins, such as manganese superoxide dismutase. As part of the BU Cardiovascular Proteomics Center, Dr. Cohen and his group are identifying chemical modifications of proteins formed by oxidants with mass spectrometric and protein tagging strategies. These modifications may serve as biomarkers for abnormal cell signaling and/or disease. Such markers have been found in diseased human arteries and platelets.

References:

Ying J, Sharov V, Xu S, Jiang B, Gerrity R, Schöneich C, Cohen RA. Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca(2+) ATPase in diabetic pig aorta. Free Radic Biol Med. 2008 Sep 15;45(6):756-62. Epub 2008 Jun 13. PubMed PMID: 18590812; PubMed Central PMCID: PMC2654240.
Tong X, Ying J, Pimentel DR, Trucillo M, Adachi T, Cohen RA. High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration. J Mol Cell Cardiol. 2008 Feb;44(2):361-9. Epub 2007 Nov 12. PubMed PMID:18164028; PubMed Central PMCID: PMC2394666.
Sethuraman M, Clavreul N, Huang H, McComb ME, Costello CE, Cohen RA. Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry. Free Radic Biol Med. 2007 Mar 15;42(6):823-9. Epub 2006 Dec 16. PubMed PMID: 17320764; PubMed Central PMCID: PMC1855198.
Ying J, Tong X, Pimentel DR, Weisbrod RM, Trucillo MP, Adachi T, Cohen RA.Cysteine-674 of the sarco/endoplasmic reticulum calcium ATPase is required for the inhibition of cell migration by nitric oxide. Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):783-90. Epub 2007 Jan 18. PubMed PMID: 17234728.
Clavreul N, Bachschmid MM, Hou X, Shi C, Idrizovic A, Ido Y, Pimentel D, Cohen RA. S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2454-61. Epub 2006 Aug 24. PubMed PMID: 16931794.
Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL 7. receptor-deficient mice. Diabetes. 2006 Aug;55(8):2180-91. PubMed PMID: 16873680.
Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA. Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(-/-) mice. Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):910-6. Epub 2006 Jan 26. PubMed PMID: 16439706.






			Richard Cohen, M.D. The Cell Biology of the Diseased Vessel Wall The Vascular Biology Unit led by Dr. Richard Cohen seeks to understand why oxidants impair function of diseased arteries. His group has found that in diabetes, hypertension, and atherosclerosis, the vasodilator, nitric oxide is inactivated by superoxide, an oxidant produced in diseased blood vessels. As a result of this reaction an even more potent oxidant, peroxynitrite, is formed. At low levels, peroxynitrite S-glutathiolates proteins including the sarcoplasmic reticulum calcium ATPase and p21ras, modulating cell signaling. High levels of peroxynitrite can be blamed for inactivating these and other important proteins, such as manganese superoxide dismutase. As part of the BU Cardiovascular Proteomics Center, Dr. Cohen and his group are identifying chemical modifications of proteins formed by oxidants with mass spectrometric and protein tagging strategies. These modifications may serve as biomarkers for abnormal cell signaling and/or disease. Such markers have been found in diseased human arteries and platelets. References: Ying J, Sharov V, Xu S, Jiang B, Gerrity R, Schöneich C, Cohen RA. Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca(2+) ATPase in diabetic pig aorta. Free Radic Biol Med. 2008 Sep 15;45(6):756-62. Epub 2008 Jun 13. PubMed PMID: 18590812; PubMed Central PMCID: PMC2654240. Tong X, Ying J, Pimentel DR, Trucillo M, Adachi T, Cohen RA. High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration. J Mol Cell Cardiol. 2008 Feb;44(2):361-9. Epub 2007 Nov 12. PubMed PMID:18164028; PubMed Central PMCID: PMC2394666. Sethuraman M, Clavreul N, Huang H, McComb ME, Costello CE, Cohen RA. Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry. Free Radic Biol Med. 2007 Mar 15;42(6):823-9. Epub 2006 Dec 16. PubMed PMID: 17320764; PubMed Central PMCID: PMC1855198. Ying J, Tong X, Pimentel DR, Weisbrod RM, Trucillo MP, Adachi T, Cohen RA.Cysteine-674 of the sarco/endoplasmic reticulum calcium ATPase is required for the inhibition of cell migration by nitric oxide. Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):783-90. Epub 2007 Jan 18. PubMed PMID: 17234728. Clavreul N, Bachschmid MM, Hou X, Shi C, Idrizovic A, Ido Y, Pimentel D, Cohen RA. S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2454-61. Epub 2006 Aug 24. PubMed PMID: 16931794. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL 7. receptor-deficient mice. Diabetes. 2006 Aug;55(8):2180-91. PubMed PMID: 16873680. Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA. Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(-/-) mice. Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):910-6. Epub 2006 Jan 26. PubMed PMID: 16439706.