Diastolic Dysfunction with Vascular Deficits in HIV-1-Infected Female Humanized Mice Treated with Antiretroviral Drugs

Authors

Fadhel A. Alomar, Imam Abdulrahman Bin Faisal University
Prasanta K. Dash, University of Nebraska Medical CenterFollow
Mahendran Ramasamy, University of Nebraska Medical CenterFollow
Zachary L. Venn, University of Nebraska Medical CenterFollow
Sean R. Bidasee, University of Nebraska Medical Center
Chen Zhang, University of Nebraska Medical CenterFollow
Bryan T. Hackfort, University of Nebraska Medical CenterFollow
Santhi Gorantla, University of Nebraska Medical CenterFollow
Keshore R. Bidasee, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

International Journal of Molecular Sciences

Publication Date

2025

Volume

26

Abstract

Early-onset heart failure is a major treat to healthy aging individuals with HIV-1 infection. Women with HIV-1 infection (WLWH) are especially vulnerable and develop heart failure with preserved ejection fraction (HFpEF), of which left ventricular diastolic dysfunction, vascular deficits, myocardial infarction, and fibrosis are major components. HIV-infected rodent models that exhibit these pathophysiological features remain under-reported, and this has left a void in our understanding of their molecular causes and therapeutic strategies to blunt its development. Here, we show that female NOD.Cg-Prkdc^scidIl2rgt^m1Wjl/SzJ humanized mice (Hu-mice) infected with HIV-1_ADA and treated for 13 weeks with dolutegravir (DTG)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) develop progressive diastolic dysfunction with preserved ejection fraction (E:A ratio, E:e', IVRT, left atrial volume and global longitudinal strain increased by 32.1 ± 5.1%, 28.2 ± 5.6%, 100.2 ± 12.6%, 26.6 ± 4.2% and 32.5 ± 4.3%, respectively). In vivo photoacoustic imaging revealed a 30.4 ± 6.8% reduction in saturated oxygenated hemoglobin in the anterior wall of the heart. The ex vivo analysis of hearts showed a reduction in density of perfused microvessels/ischemia (30.6 ± 6.2%) with fibrosis (20.2 ± 1.2%). The HIF-1α level was increased 2.6 ± 0.5-fold, while inflammation-induced serum semicarbazide amine oxidase and glycolysis byproduct methylglyoxal increased 2-fold and 2.1-fold, respectively. Treating H9C2 cardiac myocytes with DTG, FTC and TDF dose-dependently increased expression of HIF-1α. These data show that HIV-infected Hu-mice treated with DTG/TDF/FTC for thirteen weeks develop cardiac diastolic dysfunction, with vascular deficits, ischemia, and fibrosis like those reported in women living with HIV-1 infection (WLWH). They also show that DTG, TDF, and FTC treatment can increase total HIF-1α in H9C2 cells

MeSH Headings

Animals, Female, HIV Infections, Mice, HIV-1, Humans, Anti-Retroviral Agents, Disease Models, Animal, Mice, Inbred NOD, Ventricular Dysfunction, Left, Tenofovir, Pyridones, Heterocyclic Compounds, 3-Ring, Oxazines, Piperazines

DOI Link

10.3390/ijms26083801

ISSN

1422-0067

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Alomar, Fadhel A.; Dash, Prasanta K.; Ramasamy, Mahendran; Venn, Zachary L.; Bidasee, Sean R.; Zhang, Chen; Hackfort, Bryan T.; Gorantla, Santhi; and Bidasee, Keshore R., "Diastolic Dysfunction with Vascular Deficits in HIV-1-Infected Female Humanized Mice Treated with Antiretroviral Drugs" (2025). Journal Articles: Cellular & Integrative Physiology. 56.
https://digitalcommons.unmc.edu/com_cell_articles/56