HIV protease inhibitor-induced cardiac dysfunction and fibrosis is mediated by platelet-derived TGF-β1 and can be suppressed by exogenous carbon monoxide

PloS One
Jeffrey LaurenceJasimuddin Ahamed

Abstract

Human immunodeficiency virus (HIV) infection is an independent risk factor for cardiovascular disease. This risk is magnified by certain antiretrovirals, particularly the protease inhibitor ritonavir, but the pathophysiology of this connection is unknown. We postulated that a major mechanism for antiretroviral-associated cardiac disease is pathologic fibrosis linked to platelet activation with release and activation of transforming growth factor (TGF)-β1, and that these changes could be modeled in a murine system. We also sought to intervene utilizing inhaled carbon monoxide (CO) as proof-of-concept for therapeutics capable of regulating TGF-β1 signaling and collagen autophagy. We demonstrate decreased cardiac function indices, including cardiac output, ejection fraction and stroke volume, and prominent cardiac fibrosis, in mice exposed to pharmacological doses of ritonavir. Cardiac output and fibrosis correlated with plasma TGF-β1 levels. Mice with targeted deletion of TGF-β1 in megakaryocytes/platelets (PF4CreTgfb1flox/flox) were partially protected from ritonavir-induced cardiac dysfunction and fibrosis. Inhalation of low dose CO (250ppm), used as a surrogate for upregulation of inducible heme oxygenase/endogenous CO pathway...Continue Reading

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Citations

Oct 18, 2019·JCI Insight·Daniel BraysonCatherine M Shanahan
Mar 15, 2020·Heart Failure Reviews·Bianca Olivia Cojan-MinzatLucia Agoston-Coldea
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Mar 30, 2021·Frontiers in Immunology·Morris MadzimeHelen C Steel

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Methods Mentioned

BETA
ELISA
flow cytometry

Clinical Trials Mentioned

NCT01214187

Software Mentioned

LV Trace
VevoLab
ImageJ
Microsoft Paint

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