Abstract
Intravenous drug use (IVDU) is the major risk factor in the development of HIV-related pulmonary arterial hypertension (HRPAH); however, the pathogenesis of HRPAH in association with IVDU has yet to be characterized. Endothelial injury is considered to be an initiating factor for pulmonary vascular remodeling in animal models of PAH. Our previous study shows that simultaneous exposure to HIV-Trans-activator of transcription (Tat) and cocaine exacerbates both disruption of tight junction proteins and permeability of human pulmonary artery endothelial cells compared with either treatment alone. We here now demonstrate that this HIV-Tat and cocaine mediated endothelial dysfunction accompanies with increase in hydrogen peroxide and superoxide radicals generation and involves redox sensitive signaling pathway. Pretreatment with antioxidant cocktail attenuated the cocaine and Tat mediated disassembly of Zonula Occludens (ZO)-1 and enhancement of endothelial monolayer permeability. Furthermore, inhibition of NADPH oxidase by apocynin or siRNA-mediated knockdown of gp-91phox abolished the Tat/cocaine-induced reactive oxygen species (ROS) production, suggesting the NADPH oxidase mediated generation of oxidative radicals. In addition, ROS dependent activation of Ras and ERK1/2 Kinase was observed to be mediating the TJP-1 disassembly, and endothelial dysfunction in response to cocaine and Tat exposure. In conclusion, our findings demonstrate that Tat/cocaine -mediated production of ROS activate Ras/Raf/ERK1/2 pathway that contributes to disruption of tight junction protein leading to pulmonary endothelial dysfunction associated with pulmonary vascular remodeling.
Highlights
HIV-related pulmonary arterial hypertension (HRPAH) is a devastating non-infectious complication associated with HIV-1 infection [1,2]
Our earlier studies reveal that exposure of human pulmonary endothelial cells to both cocaine (1 mM) and Tat (25 ng/ml) results in significant loss of Zonula Occludens (ZO)-1(TJP-1) at cell periphery leading to enhanced permeability when compared with either cocaine or Tat treatment alone [7]
Our study offers in-vitro findings that HIV protein-Tat and cocaine disrupt tight junction protein, ZO-1 and induce related endothelial dysfunction via the reactive oxygen species (ROS) dependent Ras/ERK signaling pathway
Summary
HIV-related pulmonary arterial hypertension (HRPAH) is a devastating non-infectious complication associated with HIV-1 infection [1,2]. A range of 59 to 70% of HRPAH cases are reported to be in individuals who use intravenous drugs [1,3] It is evident from various case reports that abuse of cocaine and other stimulants is a possible risk factor in the development of PAH [4]. This is concerning, as cocaine is the second most commonly used illicit drug in the United States [5] and is associated with high blood pressure, vasoconstriction and atherosclerosis [6]. By examining the post-mortem lung sections of patients with HIV-infection and a history of IV drug use, we earlier demonstrated that cocaine and/or opioid use contributes to enhanced HIV-1 related pulmonary vascular remodeling [7]
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