Richard Cohen, M.D.

The Cell Biology of the Diseased Vessel Wall

The research interests of the Vascular Biology Unit center around the vascular biology of nitric oxide. The emphasis is on novel signaling mechanisms by which nitric oxide exerts its effects on cells including smooth muscle, endothelial cells and platelets and its alterations by vascular disease. Current studies are focused on the oxidative breakdown of nitric oxide and disruption of nitricoxide signaling by oxygen-derived free radicals and their effects on nitric oxide responsive proteins as mechanisms by which vascular diseases interfere with nitric oxide action. Endpoints of interest that are involved in the pathogenesis of cardiovascular disease are smooth muscle contractility, atherosclerotic lesion development, endothelial cell leukocyte adherence, and platelet aggregation. The research programs of the Unit are highly interdependent, and involve 1) basic mechanisms of ion channel and calcium regulation in vascular smooth muscle, 2) mechanisms by which nitric oxide regulates smooth muscle contractility and signaling, 3) oxidant mediators such as NADPH oxidase and their role in mediating vascular remodeling and atherosclerosis in diseased arteries, 4) oxidant stress initiated by metabolic factors in diabetic vascular disease, 5) oxidant regulation by glucose-6-phosphate dehydrogenase, 6) post-translational modification of proteins by oxidants including nitric oxide and peroxynitrite in proteins such as eNOS, prostacyclin synthase, sarcoplasmic reticulum calcium ATPase, and manganese SOD.

References:

1. Cayatte, A., Rupin, A., Oliver-Krasinski, J., Maitland, K., Sansilvestri-Morel, P., Boussard, M., Wierzbicki, M., Verbeuren, T., Cohen, R. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase. Arterioscler Thromb Vasc Biol., 21: 1577-1584, October 2001.

2. Jiang, B., Brecher, P., Cohen, R.A. Persistent activation of nuclear factor-kB by interleukin-1ß and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase. Arterioscler Thromb Vasc Biol., 21:1915-1920, 2001.

3. Wang, H.D., Johns, D.G., Xu, S., Cohen, R.A. Role of superoxide anion in regulating the pressor and vascular hypertrophic response to angiotensin II. Am J Physiol Heart Circ Physiol 282:H1697-H1702, 2002.

4. Zou, M.-H., Shi, C., Cohen, R.A. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2 receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes, 51(1):198-203, 2002.

5. Zou, M.-H., Shi, C., Cohen, R.A. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. The Journal of Clinical Investigation, 109(6): 817-826, March 2002.

6. Adachi T, Matsui R, Xu S, Kirber M, Lazar HL, Sharov VS, Schöneich C, and Cohen RA. Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca-ATPase function and lowers tyrosine nitration in hypercholesterolemia and improves nitric oxide-induced relaxation. Circulation Research 90: 1114-1121, 2002.

7. Zou,M.-H., Hou,X.Y., Shi,C.M., Nagata,D., Walsh,K., Cohen,R.A. Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. Journal of Biological Chemistry, 277(36): 32552-32557, 2002.

8. Jiang B., Xu S., Brecher P., Cohen R.A. Growth factors enhance interleukin-1â-induced persistent activation of nuclear factor-êB in rat vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 22: 1811-1816, 2002.

9. Zou MH, Hou XY, Shi CM, Kirkpatick S, Liu F, Goldman MH, Cohen RA. Activation of 5'-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J Biol Chem. 2003;278:34003-10.

10. Guo W, Adachi T, Matsui R, Xu S, Jiang B, Zou MH, Kirber M, Lieberthal W, Cohen RA. Quantitative assessment of tyrosine nitration of manganese superoxide dismutase in angiotensin II-infused rat kidney. Am J Physiol Heart Circ Physiol. 2003;285:H1396-403.

11. Jiang B, Xu S, Hou X, Pimentel DR, Cohen RA. Angiotensin II differentially regulates interleukin-1-beta-inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) expression: role of p38 MAPK. J Biol Chem. 2004;279:20363-8.

12. Sethuraman M, McComb ME, Heibeck T, Costello CE, Cohen RA. Isotope-coded affinity tag approach to identify and quantify oxidant-sensitive protein thiols. Mol Cell Proteomics. 2004;3:273-8.


	Richard Cohen, M.D. The Cell Biology of the Diseased Vessel Wall The research interests of the Vascular Biology Unit center around the vascular biology of nitric oxide. The emphasis is on novel signaling mechanisms by which nitric oxide exerts its effects on cells including smooth muscle, endothelial cells and platelets and its alterations by vascular disease. Current studies are focused on the oxidative breakdown of nitric oxide and disruption of nitricoxide signaling by oxygen-derived free radicals and their effects on nitric oxide responsive proteins as mechanisms by which vascular diseases interfere with nitric oxide action. Endpoints of interest that are involved in the pathogenesis of cardiovascular disease are smooth muscle contractility, atherosclerotic lesion development, endothelial cell leukocyte adherence, and platelet aggregation. The research programs of the Unit are highly interdependent, and involve 1) basic mechanisms of ion channel and calcium regulation in vascular smooth muscle, 2) mechanisms by which nitric oxide regulates smooth muscle contractility and signaling, 3) oxidant mediators such as NADPH oxidase and their role in mediating vascular remodeling and atherosclerosis in diseased arteries, 4) oxidant stress initiated by metabolic factors in diabetic vascular disease, 5) oxidant regulation by glucose-6-phosphate dehydrogenase, 6) post-translational modification of proteins by oxidants including nitric oxide and peroxynitrite in proteins such as eNOS, prostacyclin synthase, sarcoplasmic reticulum calcium ATPase, and manganese SOD. References: 1. Cayatte, A., Rupin, A., Oliver-Krasinski, J., Maitland, K., Sansilvestri-Morel, P., Boussard, M., Wierzbicki, M., Verbeuren, T., Cohen, R. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase. Arterioscler Thromb Vasc Biol., 21: 1577-1584, October 2001. 2. Jiang, B., Brecher, P., Cohen, R.A. Persistent activation of nuclear factor-kB by interleukin-1ß and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase. Arterioscler Thromb Vasc Biol., 21:1915-1920, 2001. 3. Wang, H.D., Johns, D.G., Xu, S., Cohen, R.A. Role of superoxide anion in regulating the pressor and vascular hypertrophic response to angiotensin II. Am J Physiol Heart Circ Physiol 282:H1697-H1702, 2002. 4. Zou, M.-H., Shi, C., Cohen, R.A. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2 receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes, 51(1):198-203, 2002. 5. Zou, M.-H., Shi, C., Cohen, R.A. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. The Journal of Clinical Investigation, 109(6): 817-826, March 2002. 6. Adachi T, Matsui R, Xu S, Kirber M, Lazar HL, Sharov VS, Schöneich C, and Cohen RA. Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca-ATPase function and lowers tyrosine nitration in hypercholesterolemia and improves nitric oxide-induced relaxation. Circulation Research 90: 1114-1121, 2002. 7. Zou,M.-H., Hou,X.Y., Shi,C.M., Nagata,D., Walsh,K., Cohen,R.A. Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. Journal of Biological Chemistry, 277(36): 32552-32557, 2002. 8. Jiang B., Xu S., Brecher P., Cohen R.A. Growth factors enhance interleukin-1â-induced persistent activation of nuclear factor-êB in rat vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 22: 1811-1816, 2002. 9. Zou MH, Hou XY, Shi CM, Kirkpatick S, Liu F, Goldman MH, Cohen RA. Activation of 5'-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J Biol Chem. 2003;278:34003-10. 10. Guo W, Adachi T, Matsui R, Xu S, Jiang B, Zou MH, Kirber M, Lieberthal W, Cohen RA. Quantitative assessment of tyrosine nitration of manganese superoxide dismutase in angiotensin II-infused rat kidney. Am J Physiol Heart Circ Physiol. 2003;285:H1396-403. 11. Jiang B, Xu S, Hou X, Pimentel DR, Cohen RA. Angiotensin II differentially regulates interleukin-1-beta-inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) expression: role of p38 MAPK. J Biol Chem. 2004;279:20363-8. 12. Sethuraman M, McComb ME, Heibeck T, Costello CE, Cohen RA. Isotope-coded affinity tag approach to identify and quantify oxidant-sensitive protein thiols. Mol Cell Proteomics. 2004;3:273-8.