Extracellular vesicle TGF-b1 is linked to cardiopulmonary dysfunction in human immunodeficiency virus

Balaji Krishnamachary, Aatish Mahajan, Ashok Kumar, Stuti Agarwal, Aradhana Mohan, Ling Chen, Priscilla Y. Hsue, Prabhakar Chalise, Alison Morris, Navneet K. Dhillon

Research output: Contribution to journalArticlepeer-review

Abstract

Extracellular vesicles (EVs) have emerged as important mediators in cell–cell communication; however, their relevance in pulmonary hypertension (PH) secondary to human immunodeficiency virus (HIV) infection is yet to be explored. Considering that circulating monocytes are the source of the increased number of perivascular macrophages surrounding the remodeled vessels in PH, this study aimed to identify the role of circulating small EVs and EVs released by HIV-infected human monocyte–derived macrophages in the development of PH. We report significantly higher numbers of plasma-derived EVs carrying higher levels of TGF-b1 (transforming growth factor-b1) in HIV-positive individuals with PH compared with individuals without PH. Importantly, levels of these TGF-b1–loaded, plasma-derived EVs correlated with pulmonary arterial systolic pressures and CD4 counts but did not correlate with the DLCO or viral load. Correspondingly, enhanced TGF-b1–dependent pulmonary endothelial injury and smooth muscle hyperplasia were observed. HIV-1 infection of monocyte-derived macrophages in the presence of cocaine resulted in an increased number of TGF-b1–high EVs, and intravenous injection of these EVs in rats led to increased right ventricle systolic pressure accompanied by myocardial injury and increased levels of serum ET-1 (endothelin-1), TNF-a, and cardiac troponin-I. Conversely, pretreatment of rats with TGF-b receptor 1 inhibitor prevented these EV-mediated changes. Findings define the ability of macrophage-derived small EVs to cause pulmonary vascular modeling and PH via modulation of TGF-b signaling and suggest clinical implications of circulating TGF-b–high EVs as a potential biomarker of HIV-associated PH.

Original languageEnglish (US)
Pages (from-to)413-429
Number of pages17
JournalAmerican journal of respiratory cell and molecular biology
Volume65
Issue number4
DOIs
StatePublished - Oct 2021
Externally publishedYes

Keywords

  • Endothelial injury
  • Inflammation
  • Monocytes
  • Pulmonary hypertension
  • Smooth muscle dysfunction

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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