10.7 - Osteopontin is an integral pro-fibrotic mediator of myocardial fibrosis in HIV infection.
Saturday, April 2, 2022
12:38 PM – 12:41 PM
Room: 118 BC - Pennsylvania Convention Center
Introduction: Session Description: As a Society, we cannot escape the identity crisis we have confronted in the past - what is pathology and how do pathologists fit into the basic framework of biomedical science? This is an ongoing challenge that requires our members to educate others regarding the nature of the discipline of experimental pathology and how our research describes and investigates the pathology, pathogenesis, and pathophysiology of specific diseases at the molecular, cellular, organ, and organismal level. Overcoming this identity crisis requires effort on the part of each ASIP member and our success will be evident as we continue to attract bright and enthusiastic young investigators into the diverse field of experimental pathobiology.
The American Society for Investigative Pathology presents I Am An ASIP Member and This Is My Science a dynamic and inspiring session featuring ASIP Scientists on the Cutting Edge of Discovery briefly, present their research, accomplishments, career journeys, and service to ASIP. This session highlights the diversity among our membership, and provides trainees, young scientists, pathologists, and the members of the larger scientific community the opportunity to become inspired by Trailblazers in the field of investigative pathology.
Jake Robinson (Lewis Katz School of Medicine), Amanda Brown (Johns Hopkins School of Medicine), Tricia Burdo (Lewis Katz School of Medicine)
With introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV) has transitioned to a chronic, progressive inflammatory disease, with increasing evidence of subclinical and early-onset cardiovascular comorbidities. PWH have a greater risk and prevalence of diastolic dysfunction compared to seronegative individuals. In a clinical cohort of ART-adherent, virally suppressed women with HIV, we showed women with HIV exhibited increased myocardial extracellular volume and reduced diastolic strain rate compared to matched seronegative women. Taken together, we hypothesize that chronic HIV infection promotes a pro-fibrotic environment in the heart, perturbing ventricular homeostatic function. First, we utilized the highly translatable simian immunodeficiency virus (SIV)-infected rhesus macaque model. We used three cohorts in our study: uninfected animals (SIV-), SIV-infected untreated animals (SIV+), and SIV-infected animals receiving a clinically relevant ART regimen (SIV+ART). Assessing fibrosis in the left ventricle, we observed greater interstitial fibrosis in SIV+ animals compared to SIV- and SIV+ART animals. We identified osteopontin as a potential fibrotic signal in the heart from its role in macrophage function, as a matricellular protein, and as an immunomodulatory cytokine. We observed significant differences in post-translational enzymatic processing of osteopontin between the three groups, and SIV+ animals showed a significant increase in full-length osteopontin compared to SIV- and SIV+ART. Lastly, we used an HIV-infected humanized mouse model to functionally inhibit osteopontin in vivo with an RNA aptamer. HIV-infected mice exhibited greater fibrotic burden in the left ventricle of the heart compared to uninfected controls. HIV-infected mice treated with an osteopontin-inhibiting RNA aptamer had reduced fibrotic content in the left ventricle compared to HIV infected mice, showing similar levels to uninfected mice. Together, these data suggest that osteopontin is an integral fibrotic signal in the heart and a potential adjunctive target in reducing HIV-associated myocardial fibrosis.
