This is a proposal dealing with medical consequences (pulmonary arterial hypertension) associated with HIV-1 and drugs of abuse. The advent of antiretroviral therapy has clearly led to improved survival among HIV-1 infected individuals yet this advancement has resulted in unexpected increase in the prevalence of vascular complications including pulmonary arterial hypertension. Development of HIV-associated PAH (HPAH) results in early mortality and serves as an independent predictor of death in patients infected with HIV-1. While intravenous drug use accounts for one-third of all new cases of AIDS in the United States, it has been identified as the most common risk factor in the individuals diagnosed with HPAH. Furthermore, our recent study showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers indicate that IVDU and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Abnormal smooth muscle cell proliferation/migration are considered to play a key role in vascular remodeling leading to increased pulmonary vascular resistance associated with PAH but the mechanisms and pathogenesis involved remain elusive. Our recent study supports an additive effect of cocaine on the HIV-Tat mediated increase in proliferation of human pulmonary arterial smooth muscle cells (pSMCs). Based on our recent strong preliminary findings we hypothesize that this Tat and cocaine mediated increase in proliferation of pSMCs involves down-modulation of anti-proliferative bone morphogenetic protein receptor (BMPR) protein expression through post-transcriptional regulation by micro-RNAs (mi-RNAs). This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV-Tat and cocaine on the BMPRs expression and its down-stream signaling pathways. In the second aim, we propose to delineate the post-transcriptional mechanism(s) involved in Tat and cocaine mediated regulation of BMPR expression, through modulation of specific miRNAs. In order to further confirm the interactions of HIV-1 and cocaine on BMPR axis, the third aim will be focused on ex-vivo and in-vivo investigation of miRNA mediated regulation of BMP/BMPR axis in pSMCs. These studies are innovative because this will be a first attempt to understand the miRNA mediated effect on anti-proliferative signaling pathways involved in the interaction of cocaine and viral protein that results in smooth muscle hyperplasia and linking these changes to the pulmonary vascular and right heart dysfunction associated with HPAH. The proposed research is significant because it will provide a more complete understanding of pathogenic mechanisms involved in the development of HPAH in the presence and absence of cocaine abuse. Thus, important advances in the development of targeted therapies and understanding of complications associated with HIV and drugs of abuse associated PAH are expected in the future which is relevant to the NIH's mission of developing fundamental knowledge that will potentially help reduce the burdens of human disability.
The proposed research will have an important positive impact on human health because the identified mechanism(s) and the molecules involved are expected to provide new targets for therapeutic interventions that will aid the growing number of HIV-infected and/or intravenous drug users, who acquire pulmonary arterial hypertension. In addition, the results will fundamentally advance the field of cardio-pulmonary vascular research in general.
