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Elevated Methylglyoxal: An Elusive Risk Factor Responsible for Early-Onset Cardiovascular Diseases in People Living
Mahendran Ramasamy1, Zachary L Venn1, Fadhel A Alomar2
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68130, USA.
Insights
Elevated methylglyoxal (MG) contributes to early cardiovascular diseases (CVDs) in people living with HIV (PLWH). Enhancing the MG-degrading enzyme glyoxalase I (Glo-I) shows promise in preventing CVDs in PLWH.
Area of Science:
- Biomedical Science
- Cardiovascular Research
- HIV Pathogenesis
Background:
- People living with HIV (PLWH) experience cardiovascular diseases (CVDs) significantly earlier and at higher rates than the general population.
- Current pharmacological strategies to prevent CVDs in PLWH are limited due to an incomplete understanding of molecular causes.
- Elevated levels of methylglyoxal (MG), a toxic byproduct of glycolysis and inflammation, have been observed in PLWH.
Purpose of the Study:
- To investigate the role of methylglyoxal (MG) in the accelerated development of cardiovascular diseases (CVDs) in people living with HIV (PLWH).
- To explore the potential of targeting MG accumulation as a therapeutic strategy for preventing early-onset CVDs in PLWH.
Main Methods:
- Analysis of plasma methylglyoxal (MG) levels in PLWH and HIV-infected humanized mice (Hu-mice).
- Assessment of glyoxalase I (Glo-I) expression in cardiac tissues from HIV-1-infected individuals and Hu-mice.
- Intervention studies in HIV-1-infected Hu-mice involving increasing Glo-I expression to evaluate its impact on cardiac function and vascular health.
Main Results:
- Reduced expression of the MG-degrading enzyme glyoxalase I (Glo-I) was found in cardiac tissues of HIV-1-infected individuals and Hu-mice.
- Increasing Glo-I expression in HIV-1-infected Hu-mice attenuated heart failure, reduced endothelial cell damage, and improved microvascular integrity.
- Elevated MG levels were identified as a contributing factor to CVDs in PLWH, with Glo-I upregulation mitigating key CVD mediators like VAP-1.
Conclusions:
- Elevated methylglyoxal (MG) is a significant contributing factor to the early onset of cardiovascular diseases (CVDs) in people living with HIV (PLWH).
- Enhancing the activity or expression of glyoxalase I (Glo-I) presents a potential therapeutic avenue to prevent or delay the development of CVDs in PLWH.
- Targeting MG accumulation offers a promising strategy for managing cardiovascular complications in the context of HIV infection.
Abstract:
People living with HIV (PLWH) develop cardiovascular diseases (CVDs) about a decade earlier and at rates 2-3 times higher than the general population. At present, pharmacological strategies to delay the onset of CVDs in PLWH are unavailable, in part because of an incomplete understanding of its molecular causes. We and others recently uncovered elevated levels of the toxic glycolysis and inflammation-induced byproduct methylglyoxal (MG) in plasma from PLWH and from HIV-infected humanized mice (Hu-mice). We also found a reduction in expression of the primary MG-degrading enzyme glyoxalase I (Glo-I) in autopsied cardiac tissues from HIV-1-infected individuals and HIV-1-infected Hu-mice. Increasing the expression of Glo-I in HIV-1-infected Hu-mice not only attenuated heart failure but also reduced endothelial cell damage, increased the density of perfused microvessels, prevented microvascular leakage and micro-ischemia, and blunted the expression of the inflammation-induced protein vascular protein-1 (VAP-1), key mediators of CVDs. In this narrative review, we posit that elevated MG is a contributing cause for the early onset of CVDs in PLWH. Pharmacological strategies to prevent MG accumulation and delay the development of early-onset CVDs in PLWH are also discussed.
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