A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection

Authors

Prasanta K. Dasg, University of Nebraska Medical Center
Fadhel A. Alomar, Imam Abdulrahman Bin Faisal University
Jesse L. Cox, University of Nebraska Medical Center
JoEllyn McMillan, University of Nebraska Medical Center
Bryan T. Hackfort, University of Nebraska Medical Center
Edward Makarov, University of Nebraska Medical Center
Brenda Morsey, University of Nebraska Medical Center
Howard S. Fox, University of Nebraska Medical Center
Howard E. Gendelman, University of Nebraska Medical Center
Santhi Gorantla, University of Nebraska Medical Center
Keshore R. Bidasee, University of Nebraska Medical Center

Date of this Version

12-14-2021

Citation

Dash PK, Alomar FA, Cox JL, McMillan J, Hackfort BT, Makarov E, Morsey B, Fox HS, Gendelman HE, Gorantla S and Bidasee KR (2021) A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection. Front. Cardiovasc. Med. 8:792180. doi: 10.3389/fcvm.2021.792180

Comments

open access

Abstract

Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg- Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma MG. At sixteen-seventeen weeks post infection, cardiac ejection fraction and fractional shortening also declined by 26 and 35%, and plasma MG increased to four-fold higher than uninfected controls. Histopathological and biochemical analyses of cardiac tissues from Hu-mice 17 weeks post-infection affirmed MG increase with a concomitant decrease in expression of the MG-degrading enzyme glyoxalase-1 (Glo1). The endothelial cell marker CD31 was found to be lower, and coronary microvascular leakage and myocardial fibrosis were prominent. Increasing expression of Glo1 in Hu-mice five weeks post-infection using a single dose of an engineered AAV2/9 (1.7 × 10¹² virion particles/kg), attenuated the increases in plasma and cardiac MG levels. Increasing Glo1 also blunted microvascular leakage, fibrosis, and HF seen at sixteen weeks post-infection, without changes in plasma viral loads. In plasma fromvirally suppressed PLWH,MG was also 3.7-fold higher. In autopsied cardiac tissues from seropositive, HIV individuals with low viral log, MG was 4.2-fold higher and Glo1 was 50% lower compared to uninfected controls. These data show for the first time a causal link between accumulation of MG and HF in the setting of HIV infection.