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

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-PrkdcscidIl2rgtm1Wjl/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 from virally 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.

HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2)

“…At high heart rates, cardiac fibrosis can lead to early after depolarizations (EADs), which are harbingers for atrial fibrillation (AF) [28] and ventricular fibrillation (VF) [29]. We also reported correlations between myocardial fibrosis, endothelial dysfunction microvasculature leakage, and ischemia in the hearts of HIV-1-infected humanized mice [30].…”

Elevated plasma level of the glycolysis byproduct methylglyoxal on admission is an independent biomarker of mortality in ICU COVID-19 patients

“…Supraphysiological levels of MG will also potentiate inflammation in many cell types by activating NF-κB 46 , the NLR family pyrin domain containing 3 (NRLP3) inflammasome 47 , and by inducing expression of the ectoenzyme vascular adhesion protein 1 and its cleaved analog semicarbazide-sensitive amine oxidase (SSAO) 48 . Elevated MG is also an underlying cause for tissue fibrosis 49 , a pathobiology reported in COVID-19 patients.…”

Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

“…These modifications interfere with protein interaction with muscle and disrupt calcium sensitivity, both processes that are critical for proper cardiac function . In a study of comorbidity with HIV infection, a positive association between MG in the heart and plasma and an enhanced risk for heart failure was observed . Moreover, higher plasma MG levels were consistently associated with fatal cardiovascular events in individuals with type 1 diabetes (T1D) .…”

“… 147 In a study of comorbidity with HIV infection, a positive association between MG in the heart and plasma and an enhanced risk for heart failure was observed. 148 Moreover, higher plasma MG levels were consistently associated with fatal cardiovascular events in individuals with type 1 diabetes (T1D). 149 A similar finding was also made in individuals with type 2 diabetes (T2D) with elevated plasma MG associated with higher risk for atherosclerosis and high blood pressure, spurring interest in its utility as a predictive biomarker for heart disease.…”