Downregulation of Bone Morphogenetic Protein Receptor Axis During HIV-1 and Cocaine-Mediated Pulmonary Smooth Muscle Hyperplasia

Abstract

Objective Our previous findings support an additive effect of cocaine to HIV-infection in the development of pulmonary arteriopathy through enhanced proliferation of human pulmonary smooth muscle cells. We now examined the role of anti-proliferative bone morphogenetic protein receptor (BMPR) axis in HIV-protein and cocaine mediated pulmonary smooth muscle hyperplasia. Approach and Results Stimulation of BMPR axis resulted in attenuation of synergistic increase in the proliferation of human pulmonary arterial smooth muscle cells in response to cocaine and HIV protein, Trans-Activator of Transcription (Tat). Interestingly, an increase in mRNA but decrease in protein levels of BMPR with correlated decrease in the activation of SMAD1/5/8 and Id1 gene expression was observed on combined treatment with cocaine and Tat compared to untreated cells at all-time points tested. Although longer exposure to either cocaine or Tat alone also resulted in a significant decrease in the BMPR protein expression, the abrogation on combined treatment was still significantly more compared to mono-treatments. Significant increase in mRNA but down-modulation of BMPR protein expression was also observed in the lung extracts from HIV-infected intravenous drug users (HIV+IVDU) when compared with HIV-infected non-IVDUs (HIV) or un-infected IVDUs (IVDU). Furthermore, significant decrease in BMPR protein expression was also observed in HIV or IVDUs compared to normal controls that correlated with in-vitro findings on chronic exposure to cocaine or HIV protein alone. Conclusion Simultaneous exposure of pulmonary smooth muscle cells to viral protein(s) and cocaine exacerbates down-regulation of BMPR axis that may results in enhanced pulmonary vasculature aberrations in HIV+IVDUs.

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

“…The present study contributes toward understanding our previous, consistent findings showing enhanced pulmonary vascular dysfunction in IVDUs infected with HIV compared with uninfected non-drug users or uninfected IVDUs (10,11,28,37). Here, we add new significant mechanistic details to support our earlier observation of uncontrolled proliferation of pulmonary SMCs associated with vascular remodeling in the presence of HIV proteins and illicit drugs.…”

Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine: Role in HIV-related pulmonary arterial hypertension

“…Quantitative RT-PCR was performed for checking the expression of ULK1, BECN1, ATG5, ATG7 and MAP1LC3B using SYBR green reagent as mentioned in our previous publications. 8 …”

“…[4][5][6][7] Our previous findings consistently suggest augmentation of pulmonary arteriopathy and endothelial dysfunction in HIV-infected IVDUs (mainly opioids and/or cocaine abusers) compared to HIV-infected nondrug users or uninfected IVDUs. [8][9][10][11] Our previous study on lung tissues from simian immunodeficiency virus (SIV)-infected macaques exposed to morphine, an opioid (VM group), demonstrates significant pulmonary vascular remodeling including the presence of earlyand advanced-stage complex (plexiform) lesions when compared with either the SIV-infected (V group) or morphinetreated uninfected (M group) macaques. 10 Furthermore, the pulmonary endothelial cells (pECs) lining the vessels showing medial hypertrophy or initial stage intimal lesions in lung sections from VM macaques demonstrated an increase in positivity for both TUNEL (apoptosis marker) and MKI67 (proliferation marker).…”

Vascular Function

“…Xiao et al 22 demonstrated the potential therapeutic use of the soluble Jagged1 because it not only inhibits proliferation of pulmonary VSMCs but also restores VSMCs phenotype from the dedifferentiated to the differentiated state through interference with Notch-Herp2 signaling. Finally, Dalvi et al 23 showed that simultaneous exposure of pulmonary VSMCs to viral proteins and cocaine exacerbates…”