Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations

Abstract

Dicarbonyl stress is a dysfunctional state consisting in the abnormal accumulation of reactive α-oxaldehydes leading to increased protein modification. In cells, post-translational changes can also occur through S-glutathionylation, a highly conserved oxidative post-translational modification consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue. This review recapitulates the main findings supporting a role for dicarbonyl stress and S-glutathionylation in the pathogenesis of cerebrovascular diseases, with specific emphasis on cerebral cavernous malformations (CCM), a vascular disease of proven genetic origin that may give rise to various clinical signs and symptoms at any age, including recurrent headaches, seizures, focal neurological deficits, and intracerebral hemorrhage. A possible interplay between dicarbonyl stress and S-glutathionylation in CCM is also discussed.

Keywords: S-glutathionylation; advanced glycation end products; cerebral cavernous malformations; cerebrovascular disease; dicarbonyl stress; glutathione; glyoxalase 1; methylglyoxal; oxidative stress.

Figure 1

Schematic model of the glyoxalase system. The glyoxalase system consists of two glyoxalase enzymes, Glyoxalase 1 (Glo1) and Glyoxalase 2 (Glo2), and a catalytic amount of glutathione (GSH). Glo1 converts the hemithioacetal spontaneously formed between methylglyoxal (MG) and GSH to S-D-lactoylglutathione (SLG), whereas Glo2 catalyses the hydrolysis of SLG to D-lactate (D-LAC), regenerating GSH.

Figure 2

Potential interplay between methylglyoxal (MG)-mediated glycation and S-glutathionylation pathways induced by KRIT1 (Krev interaction trapped 1) loss-of-function. The impairement of intracellular redox homeostasis caused by KRIT1 loss-of-function leads to a reactive oxygen species (ROS)-dependent sustained activation of the JNK-Nrf2 (c-Jun N-terminal kinase -nuclear factor erythroid 2-related factor) pathway and upregulation of downstram targets, including Glyoxalase 1 (Glo1). In turn, Glo1 upregulation results in decreased intracellular levels of cytoprotective MG adducts, including argpyrimidine (AP)-modified heat-shock proteins (HSP) 27 and 70, leading to an increased cell susceptibility to oxidative damage and mitochondria-dependent apoptosis. Concomitantly, KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in the GSH:GSSG redox ratio and an increase in the S-glutathionylation of important structural and regulatory proteins, including metabolic enzymes; cytoskeletal proteins; and chaperonines, such as the HSP60. A potential interplay between the MG-mediated glycation and S-glutathionylation pathways may also occur, including the modulation of the GSH:GSSG redox ratio by MG and the contribution of S-glutathionylation to ROS production and Nrf2 activation (hatched red lines), leading to a synergistic contribution to the chronic adaptive redox homeostasis and enhanced cell susceptibility to oxidative stress associated with KRIT1 loss-of-function mutations. Eventually, these synergistic pathological effects might therefore culminate in cerebral cavernous malformation (CCM) disease onset and severity. See text for details.