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 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.

Highlights

  • Human immunodeficiency virus (HIV) infection is an independent risk factor for cardiovascular disease (CVD) [1]

  • We focused on platelet-derived transforming growth factor (TGF)-β1 in a study of antiretroviral therapies (ART)-linked cardiac dysfunction and fibrosis because: platelets contain 40–100 times the concentration of TGF-β1 as other cells; it is rapidly released upon platelet activation; it is a major component of circulating TGF-β1; and it contributes to cardiac fibrosis in a mouse model of heart failure [14,15]

  • Our studies document the importance of TGF-β1, derived from platelets activated by the HIV protease inhibitor ritonavir, in cardiac dysfunction that is potentially mediated by fibrosis

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Summary

Introduction

HIV infection is an independent risk factor for cardiovascular disease (CVD) [1]. Its incidence is elevated in HIV-infected individuals receiving certain antiretroviral therapies (ART), with a relative risk for advancing carotid artery intima-medial thickness, a subclinical marker for atherosclerosis, of 13.6 for those exposed to HIV protease inhibitors (PI) [2] The PI ritonavir (RTV) has a strong correlation with CVD. Duration of RTV-boosted PI treatment was the only significant association for CVD among HIV-infected adolescents [3]. Biomarkers for CVD risk that are elevated following RTV initiation often fail to normalize following its discontinuation [4,5]. Arterial inflammation directly correlates with biomarkers of inflammation and monocyte activation, but not with markers of HIV activity, in HIV-infected individuals on ART [6] There are multiple pathways by which HIV/ART could promote CVD; we investigated cardiac fibrosis and its link to antiretroviral medications for three reasons: 1. Arterial inflammation directly correlates with biomarkers of inflammation and monocyte activation, but not with markers of HIV activity, in HIV-infected individuals on ART [6]

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