Elevated Methylglyoxal: An Elusive Risk Factor Responsible for Early-Onset Cardiovascular Diseases in People Living with HIV-1 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.

Keywords: HIV-1; aldehyde dehydrogenase; aldo-keto reductase; antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2); cardiovascular diseases; glutathione; glyoxalase-I; methylglyoxal; nicotinamide adenine dinucleotide; nicotinamide adenine dinucleotide phosphate.

Figure 1

Illustration of the HIV-1 life cycle, which is divided into two main phases: an early phase and a late phase. The early phase consists of several sequential steps: (i) HIV initially attaches to the cell via its envelope glycoproteins, gp120 and gp41, which bind to the CD4 receptor on the cell surface; (ii) gp120 and gp41 then engage with chemokine receptors, CXCR4 and CCR5, facilitating fusion with the cell membrane and viral entry; (iii) once inside, the HIV-1 capsid uncoats in the cytoplasm, releasing HIV-1 RNA, reverse transcriptase (to convert HIV RNA into HIV DNA), and integrase (to integrate HIV DNA into the host cell’s DNA) (left side). The late phase includes the steps following the integration of HIV-1 DNA into the host DNA: (i) transcription of HIV genes; (ii) export of HIV-1 RNAs from the nucleus to the cytoplasm and translation of these RNAs to produce Gag and GagPol precursor polyproteins, envelope glycoproteins, and regulatory and accessory proteins; (iii) transport of Gag, GagPol, and envelope glycoproteins to the plasma membrane; (iv) assembly of the Gag and GagPol polyproteins on the host cell’s plasma membrane; (v) encapsidation of the viral RNA genome by the forming Gag lattice; (vi) incorporation of viral Env glycoproteins; and (vii) budding of new virions from the host cell, followed by particle maturation (right side).

Figure 2

Illustration of the roles of glycolysis, fatty acids, and glutamine in cellular metabolism. In CD4⁺-T cells, glucose uptake initiates glycolysis, producing two molecules of ATP and two molecules of pyruvate. The pyruvate is then transported into the mitochondria, entering the tricarboxylic acid (TCA) cycle, where it generates NADH and FADH₂. These molecules drive oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC), resulting in the production of up to 16 molecules of ATP per molecule of pyruvate.

Figure 3

Illustration showing that HIV replication results in the synthesis of methylglyoxal (MG) via the glycolysis pathway. Additionally, MG is produced by the inflammation-induced ectoenzyme vascular adhesion protein 1 (VAP-1) through the breakdown of aminoacetone. This process is particularly important, as VAP-1 is upregulated in the vasculature, particularly in vascular smooth muscle cells, leading to elevated localized concentrations of MG near vascular endothelial cells.

Figure 4

Illustration of the detoxification of methylglyoxal (MG) through the glyoxalase system. The main pathway for methylglyoxal (MG) degradation involves the two-enzyme glyoxalase system. In the initial step, the rate-limiting enzyme glyoxalase-1 (Glo1) catalyzes the conversion of a hemithioacetal formed between MG and reduced glutathione (MG-GSH) into S,D-lactoylglutathione. Subsequently, the second enzyme, glyoxalase-2 (Glo2), acts in the presence of water to degrade S,D-lactoylglutathione into D-lactic acid and glutathione (GSH).

Figure 5

Illustration of the detoxification of methylglyoxal (MG) through oxidation by aldehyde dehydrogenases (ALDHs). This class of enzymes is responsible for the NAD(P)-dependent oxidation of aldehydes, including MG, into carboxylic acids. ALDHs facilitate the oxidation of MG to pyruvate in a NAD-dependent manner.

Figure 6

Illustration of the detoxification of methylglyoxal (MG) through reduction in the presence of reduced glutathione (GSH). The efficiency of MG reduction by aldehyde dehydrogenases (ALDHs) increases, but the reduction site shifts from the aldehyde to the ketone carbonyl. This shift occurs because glutathione modifies ALDHs, converting them from aldehyde reductases to ketone reductases. Further metabolism of the resulting lactaldehyde and acetol by aldo-keto reductase (AKR) leads to the production of propanediol.

Figure 7

Illustration demonstrating that aldo-keto reductase (AKR) can degrade methylglyoxal (MG) but also indirectly promotes MG production by increasing the production of the triose phosphate intermediate dihydroxyacetone phosphate (DHAP). Aldose reductase (AR), the first enzyme in the polyol pathway, reduces glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. Fructose is then phosphorylated to fructose-1-phosphate by ketohexokinase, which is further converted to DHAP by fructose bisphosphate aldolase. Alternatively, fructose can be phosphorylated to fructose-6-phosphate by hexokinase, which is then converted to fructose-1,6-bisphosphate by phosphofructokinase-1; this compound is subsequently converted to DHAP by fructose bisphosphate aldolase. DHAP can yield MG.

Figure 8

Illustration showing the formation of methylglyoxal (MG) adducts on proteins. When MG levels are elevated, it irreversibly reacts with accessible arginine, lysine, and histidine residues on proteins. This reaction with arginine results in the formation of three hydroimidazolone adducts: MG-H1, MG-H2, and MG-H3. Methylglyoxal (MG) also reacts with arginine to form N^δ-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-L-ornithine, known as argpyrimidine (AP), and N^δ-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine, known as tetrahydropyrimidine (THP).

Figure 9

Illustration showing pharmacological strategies to blunt MG accumulation.