1. Hyperactive TGF-β Signaling in Smooth Muscle Cells Exposed to HIV-protein(s) and Cocaine: Role in Pulmonary Vasculopathy.
- Author
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Dalvi P, Sharma H, Konstantinova T, Sanderson M, Brien-Ladner AO, and Dhillon NK
- Subjects
- Animals, Bone Morphogenetic Protein Receptors, Type II genetics, Bone Morphogenetic Protein Receptors, Type II metabolism, Cell Proliferation, Disease Models, Animal, HIV Infections metabolism, HIV Infections virology, Humans, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Pulmonary Artery metabolism, Rats, Rats, Transgenic, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta metabolism, Smad Proteins metabolism, Viral Proteins pharmacology, tat Gene Products, Human Immunodeficiency Virus metabolism, tat Gene Products, Human Immunodeficiency Virus pharmacology, Cocaine pharmacology, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Signal Transduction drug effects, Transforming Growth Factor beta metabolism, Viral Proteins metabolism
- 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.
- Published
- 2017
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