Hyperhomocysteinemia is recognized as an important risk factor for atherosclerosis. Although it is speculated that homocysteine-induced endothelial cytotoxicity may initiate lesion formation, the molecular basis of this phenomenon is unclear. We postulated and confirmed that the well-described endothelial cell loss induced by homocysteine involves the induction of apoptosis. Our hypothesis proposes that exposure of the endothelium to homocysteine promotes an alteration in vascular oxidative state which activates the genetic program governing cell suicide. Further, we hypothesize that the induction of endothelial apoptosis is the critical initiating event in the process of lesion formation. Initial experiments will characterize the role of redox-sensitive mechanisms are critical mediators of homocysteine-activated apoptosis. Specifically, we will test the hypothesis that homocysteine-induced generation of hydrogen peroxide stimulates the redox-sensitive signaling kinase, SAPK, which is coupled to the activation of the endothelial death program. These observations will be extended to a hyperhomocysteinemic transgenic mouse model to examine the role of apoptosis in the pathogenesis of homocysteine-induced vascular disease. These studies will define whether homocysteine-induced oxidative stress and endothelial apoptosis are essential initial steps in the pathogenesis of lesion formation. We will use a newly developed endothelium-specific promoter construct to target anti-apoptotic and anti-oxidant genes to render the endothelium resistant to oxidative stress and the induction of apoptosis. This project will provide a superb training experience in using state-of-the-art molecular genetic approaches to address an important yet poorly understood problem in vascular biology.
| Oakkar, Eva Erber; Stevens, June; Truesdale, Kimberly P et al. (2015) BMI and all-cause mortality among Chinese and Caucasians: the People's Republic of China and the Atherosclerosis Risk in Communities Studies. Asia Pac J Clin Nutr 24:472-9 |
| Bradshaw, Patrick T; Monda, Keri L; Stevens, June (2013) Metabolic syndrome in healthy obese, overweight, and normal weight individuals: the Atherosclerosis Risk in Communities Study. Obesity (Silver Spring) 21:203-9 |
| Stevens, June; Erber, Eva; Truesdale, Kimberly P et al. (2013) Long- and short-term weight change and incident coronary heart disease and ischemic stroke: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 178:239-48 |
