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

• Published in: PloS one Vol. 12; no. 10; p. e0187185
• Main Authors: Laurence, Jeffrey, Elhadad, Sonia, Robison, Tyler, Terry, Hunter, Varshney, Rohan, Woolington, Sean, Ghafoory, Shahrouz, Choi, Mary E, Ahamed, Jasimuddin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2017; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Activation; Adapter proteins; AIDS; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Antiviral agents; Autophagy; Biochemistry; Biology and Life Sciences; Biomarkers; Blood platelets; Blood Platelets - drug effects; Blood Platelets - metabolism; Carbon monoxide; Carbon Monoxide - pharmacology; Cardiac output; Cardiac Output - drug effects; Cardiovascular disease; Cardiovascular diseases; Clonal deletion; Collagen; Coronary artery disease; Cytokines; Drug therapy; Echocardiography; Fibrosis; Flox; Gene deletion; Growth factors; Health risks; Heart; Heart diseases; Heart Diseases - chemically induced; Heart Diseases - prevention & control; Hematology; Heme; HIV; HIV Protease Inhibitors - adverse effects; Human immunodeficiency virus; Immunoregulation; Infections; Inflammation; Inhalation; Insulin resistance; Lymphocytes T; Macrophages; Medical research; Medicine and Health Sciences; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Mouse devices; Myocardium - pathology; Oncology; Oxidative stress; Oxygenase; Pathophysiology; Phagocytosis; Pharmacology; Platelets; Protease; Protease inhibitors; Research and Analysis Methods; Respiration; Risk factors; Ritonavir; Ritonavir - adverse effects; Signal transduction; Signaling; Smad2 protein; Stroke; Stroke volume; Stroke Volume - drug effects; Transforming growth factor; Transforming Growth Factor beta1 - blood; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Viruses; New York; United States > US; Oklahoma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187185

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 pathways, suppressed ritonavir-induced cardiac fibrosis. This occurred in association with modulation of canonical (Smad2) and non-canonical (p38) TGF-β1 signaling pathways. In addition, CO treatment suppressed the M1 pro-inflammatory subset of macrophages and increased M2c regulatory cells in the hearts of RTV-exposed animals. The effects of CO were dependent upon autophagy as CO did not mitigate ritonavir-induced fibrosis in autophagy-deficient LC3-/- mice. These results suggest that platelet-derived TGF-β1 contributes to ritonavir-associated cardiac dysfunction and fibrosis, extending the relevance of our findings to other antiretrovirals that also activate platelets. The anti-fibrotic effects of CO are linked to alterations in TGF-β1 signaling and autophagy, suggesting a proof-of-concept for novel interventions in HIV/antiretroviral therapy-mediated cardiovascular disease.