Recent research has lead to an increase in knowledge of the HIV virus and its mechanism of invading cells, which has lead to the development of effective therapies to retard the progression of the disease. This success has meant that HIV patients are livi ng longer and have become the fastest-growing cardiovascular disease population in the world. An understanding of the mechanisms involved and therapies for these HIV-induced cardiovascular problems are urgently required. This proposal examines the role o f oxidative stress and poly (ADP-ribose) activation in HIV envelope-protein mediated endothelial cell (EC) dysfunction. It determines whether therapies, developed to combat such activation, will be suitable for HIV-mediated cardiovascular disease. Specific ally, the aims of this project are (1) to investigate the effect of the HIV envelope proteins TAT and GP120 on vasorelaxation of ex vivo rat aortic rings in response to acetylcholine. Using specific inhibitors of oxidative stress, superoxide dismutase mime tics, and the PARP-specific enzyme inhibitor PJ-34, we will determine the extent of involvement of these pathways in vasculature dysfunction induced by HIV proteins. (2) We will also perform studies on isolated endothelial cells treated with HIV proteins t o determine specific cellular effects mediated by oxidative stress and PARP activation. The cellular effects to be investigated include viability, energetic status and expression of pro-inflammatory mediators. (3) We will use tissue from novel transgenic animals, including the PARP and NF-?ß knockout mouse, to further study the signalling pathways and possible intervention points in cardiovascular cells affected by HIV proteins. In conclusion, the data obtained from this proposal will greatly advance the knowledge about HIV-mediated cardiovascular dysfunction and possible therapies to combat this growing problem.
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