Physicians have recommended modulation of cyclooxygenase activity to patients complaining of pain and inflammation for more than a hundred years, and for the most part unwittingly so. When Felix Hoffman initiated the production of acetylsalicylic acid (aspirin), he produced the first of many non-steroidal anti-inflammatory drugs. However, it was not until 1971 that Vane proposed experimentally that inhibition of prostaglandin synthesis was the mechanism of these agents.  Since then, we have learned that the cyclooxygenases, also known as prostaglandin endoperoxide synthases or PGH synthases, catalyze what is generally understood to be the rate-limiting step in prostaglandin synthesis from arachidonic acid.

Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins from arachidonic acid. We have previously shown that COX-2 is transcriptionally regulated by hypoxia in human umbilical vein endothelial cells in culture via the transactivation factors NF-kappaB p65, HMG I(Y), and Sp1, leading to increased production of PGE2. Using experiments at the molecular and cellular level, we propose to extend our previous work to test the hypothesis that local hypoxia is proinflammatory and antiproliferative in the vascular smooth muscle via COX-2. We plan to define mechanisms of in vascular smooth muscle exposed to hypoxia in vitro. We will study cellular expression of the COX-2 gene, including cardiovascular COX-2 synthesis and metabolism, cyclooxygenase function, prostaglandin formation, and indices of inflammation and proliferation in vascular smooth muscle cells from both murine and human sources while extending our previous studies on the nuclear signaling mechanisms of hypoxia-induced NF-kappaB-mediated transactivation.

VCIRC.ORG has been created to foster, promote and direct a translational basic science research program that will initially study the roles of COX-2 expression, activity and pharmacologic inhibition in cardiovascular diseases related to ischemia or hypoxia.  Given that oxygen, inflammation and modulation of cellular proliferation are features of cardiovascular disease that are linked, we propose to fill important gaps in our understanding of cardiopulmonary and vascular diseases where oxygen supply is inadequate, such as chronic ischemic cardiomyopathy, a public health problem that is an increasingly prevalent cause of morbidity and mortality among the aged, and its precursor, generally referred to as ischemic cardiovascular disease. Findings obtained through the work of VCIRC.ORG will be of relevance to the development of redox-sensitive gene expression technologies in experimental therapeutics. VCIRC.ORG will initiate a long-term study of cardiovascular diseases related to abnormal cellular oxygenation.

Recent progress on this subject was recently succinctly reviewed by Cormac Taylor, Ph.D. of the University College Dublin Conway Institute, as referenced below. Prof. Taylor has built an impressive body of work as of late based on the consequences of hypoxia induced gene expression mediated by NF-kappaB and HIF-1 as well as other modulators of cell responses to hypoxia that have therapeutic potential, such as the prolyl hydroxylases. VCIRC.ORG looks forward to a new collaboration with Prof. Taylor and others who see the potential for meaningful scientific progress through study of the adaptive power of the many cellular responses to hypoxia.

VCIRC.ORG has recruited Yong Woo Lee, Ph.D. to its Board of Directors. We are pleased to have him as a colleague and collaborator as well. Prof. Lee has a distinguished record of research on the cellular and molecular mechanisms of inflammatory vascular diseases. He has a particular interest in the mechanistic relationship between interleukin-4, oxidative stress, vascular inflammation and atherosclerosis. He has developed innovative techniques for exposure of cells in culture to environmental stresses. His lab has demonstrated world-class expertise in defining cellular adaptations to stress through the imaging of molecular messengers in whole cells. Prof. Lee and his lab have become a key part of the VCIRC.ORG translational research experience for our undergraduate research program participants.

Selected Bibliography:

•    Schmedtje, J.F., Jr., Liu, W.-L., Ji, Y.-S., Thompson, T.M., Runge, M.S. “Evidence of hypoxia-inducible factor-1 in vascular endothelial and smooth muscle cells.” Biochemical and Biophysical Research Communications, 1996; 220:687-691.
•    Schmedtje, J.F., Jr., Liu, W.-L., Chen, Y. “pH is critical to the regulation of expression of the beta2-adrenergic receptor gene in hypoxia." Biochimica et Biophysica Acta, 1996; 1314:25-33.
•    Schmedtje, J.F., Jr., Ji, Y.-S., Liu, W.-L., DuBois, R.N., Runge, M.S. “Hypoxia induces cyclooxygenase-2 via the NF-kappaB  p65 transcription factor in human vascular endothelial cells.” Journal of Biological Chemistry, 1997; 272:601-608.
 •    Schmedtje, J.F., Jr. and Ji, Y-S. “Hypoxia and molecular cardiovascular medicine.” Trends in Cardiovascular Medicine, 1998; 8:24-33.
 •    Ji, Y.-S. Xu, Q., Schmedtje, J.F., Jr., “Hypoxia induces HMG I(Y) and transcription of the cyclooxygenase-2 gene in human vascular endothelium.” Circulation Research, 1998; 83:295-304.
•    Xu, Q., Ji, Y.-S., Schmedtje, J.F., Jr. " Sp1 increases expression of cyclooxygenase 2 in hypoxic vascular endothelium. Implications for the mechanisms of aortic aneurysm and heart failure." Journal of Biological Chemistry, 2000; 275:24583-24589.
•    Taylor, C.T., Cummins, E.P. “The role of NF-kappaB in hypoxia-induced gene expression.” Annals New York Academy of  Sciences, 2009; 1177: 178-84.
•    Lee YW, Lee WH, Kim PH. “Oxidative mechanisms of IL-4-induced IL-6 expression in vascular endothelium.” Cytokine. 2010; 49:73-79.
•    Lee YW, Lee WH, Kim PH. “Role of NADPH oxidase in interleukin-4-induced monocyte chemoattractant protein-1 expression in vascular endothelium.” Inflammation Research Inflamm Res. 2010; 59:755-765.