Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

Ming-Lei Guo,Callen E Shannon,Yeon Hee Kook,Shilpa Buch

doi:10.1038/s41420-018-0087-9

Abstract

The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.

Highlights

In the era of combined anti-retroviral therapy, HIV (+) infection has transitioned from a life-threatening disease into a chronic, manageable disease owing to efficient suppression of plasma viremia with viral loads often below the threshold of detection[1,2]
Our findings showed that TAT exposure increased proliferation of Pulmonary artery smooth muscle cells (PASMCs) by activing Notch[3] signaling followed by increased expression of vascular endothelial growth factor A (VEGF-A)
HIV-TAT-mediated proliferation of human PASMCs Epidemiological studies indicate that the incidence of pulmonary arterial hypertension (PAH) in HIV(+) individuals is as high as 25 fold compared with the HIV(−) controls[9,10]

Summary

Introduction

In the era of combined anti-retroviral therapy (cART), HIV (+) infection has transitioned from a life-threatening disease into a chronic, manageable disease owing to efficient suppression of plasma viremia with viral loads often below the threshold of detection[1,2]. Gp[120] was shown to significantly increase the secretion of vasoconstrictor endothelin-1, a wellestablished molecule implicated in the pathogenesis of PAH, in human lung endothelial cells[19]. Another critical viral protein, TAT, has been shown to enhance the development of PAH. TAT can induce the expression of hypoxia-inducible factor-1α (HIF-1α) protein, as well as the smooth muscle cell mitogen, plateletderived growth factor-B (PDGF-B) in endothelial cells[22], both mediators that are critical for the initiation and sustenance of proliferation pathways, contributing to pulmonary vascular remodeling and the development of PAH23

Methods

Results

Conclusion