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1 Physiology & Biophysics, University of Louisville, Louisville, KY, USA
* To whom correspondence should be addressed. E-mail: s0tyag01{at}louisville.edu.
Hyperhomocysteinemia decreases vascular reactivity and is associated with cardiovascular morbidity and mortality. However, pathogenic mechanisms which increase oxidative stress by homocysteine (Hcy) are unsubstantiated. The aim of this study was to examine the molecular mechanism by which Hcy triggers oxidative stress and reduces the NO bioavailability in cardiac microvascular endothelial cells (MVEC). MVEC were cultured with different doses of Hcy at various time intervals. Differential expression of protease activated receptors (PARs), thioredoxin (Trx), NADPH oxidase (Nox1), eNOS, iNOS, nNOS and dimethylarginine-dimethylaminohydrolase (DDAH) were measured by real time Q-RT-PCR. Reactive oxygen species (ROS) were measured using a fluorescent probe, 2'-7' dichloroflurescein diacetate (DCFH-DA). Levels of asymmetric-dimethylarginine (ADMA) were measured by ELISA and NO levels were measured by Griess method in the cultured MVEC. There were no alterations in the basal NO levels with different dose of Hcy and at different time intervals. However, Hcy significantly induced iNOS and decreased eNOS, without altering nNOS levels. There was significant accumulation of ADMA, which was in part due to the reduced DDAH expression by Hcy in MVEC. Nitro-tyrosine expression was increased significantly by Hcy. The results suggest that Hcy activates PAR-4 induces the ROS production by increasing Nox1 and decreasing Trx expression, and reduces the NO bioavailability in the cultured MVEC by 1) increasing NO2-tyrosine formation; and 2) accumulating ADMA by decreasing the DDAH expression.
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