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1 Center of Cardiovascular Medicine, Columbus Childre's Research Institute, USA; Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
2 Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio, USA
3 Department of Pediatrics, College of Medicine, Ohio State University, Columbus, Ohio, USA
4 Center of Cardiovascular Medicine, Columbus Childre's Research Institute, USA; Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio, USA; Department of Pediatrics, College of Medicine, Ohio State University, Columbus, Ohio, USA
* To whom correspondence should be addressed. E-mail: baligar{at}ccri.net.
Increased life expectancy of HIV+ patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine AIDS model and evaluated potential mechanisms in both murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation, and/or endothelial protein nitration and their association with time dependent vascular dysfunction. At 1 and 5 weeks of MAIDS, statistically significant decreases in KCL contractility and time dependent contractile deficits in response to phenylephrine were observed. Emax reduced by approximately 40% at 10 weeks, and EC50 values significantly changed(102±7.3ng control vs.190±37ng at 5 weeks vs. 130±22ng at 10weeks, p<0.05). Endothelium dependent relaxation to ACH was decreased (EC50 control 120±27nM vs. 343±94nM at 10 weeks), while the response to an exogenous NO donor SNP remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations into the same tissues showed increased protein 3NT, ICAM, NOS-2 and NOS-3. These findings were corroborated in concurrent experiments in a cohort of well-catalogued human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS, which was also associated with and correlated to increased oxidative stress and specific endothelial activation. Finally, this finding was echoed in a relevant population of human HIV/AIDS patients. Research into the sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.
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