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Hyperactive TGF-β Signaling in Smooth Muscle Cells Exposed to HIV-protein(s) and Cocaine: Role in Pulmonary Vasculopathy.

Hyperactive TGF-β Signaling in Smooth Muscle Cells Exposed to HIV-protein(s) and Cocaine: Role in Pulmonary Vasculopathy.
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Dalvi P, Sharma H, Konstantinova T, Sanderson M, Brien-Ladner AO, Dhillon NK,


Dalvi P, Sharma H, Konstantinova T, Sanderson M, Brien-Ladner AO, Dhillon NK, (click to view)

Dalvi P, Sharma H, Konstantinova T, Sanderson M, Brien-Ladner AO, Dhillon NK,

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Scientific reports 2017 09 057(1) 10433 doi 10.1038/s41598-017-10438-3

Abstract

We earlier demonstrated synergistic increase in the proliferation of pulmonary smooth muscle cells on exposure to HIV-proteins and/or cocaine due to severe down-modulation of bone morphogenetic protein receptor (BMPR) axis: the anti-proliferative arm of TGF-β super family of receptors. Here, now we demonstrate the effect of HIV-Tat and cocaine on the proliferative TGF-β signaling cascade. We observed a significant increase in the secretion of TGF-β1 ligand along with enhanced protein expression of TGFβ Receptor (TGFβR)-1, TGFβR-2 and phosphorylated SMAD2/3 in human pulmonary arterial smooth muscle cells on treatment with cocaine and Tat. Further, we noticed an increase in the levels of p-TAK1 complexed with TGFβR-2. Concomitant to this a significant increase in the activation of TAK1-mediated, SMAD-independent downstream signaling molecules: p-MKK4 and p-JNK was observed. However, activation of MKK3/6-p38MAPK, another axis downstream of TAK1 was found to be reduced due to attenuation in the protein levels of BMPR2. Both SMAD and non-SMAD dependent TGFβR cascades were found to contribute to hyper-proliferation. Finally the increase in the levels of phosphorylated TGFβR1 and TGFβR2 on exposure to HIV-proteins and cocaine was confirmed in pulmonary smooth muscle cells from cocaine injected HIV-transgenic rats and in total lung extracts from HIV infected cocaine and/or opioid users.

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