Role of Nitric Oxide and Hydrogen Sulfide in Ischemic Stroke and the Emergent Epigenetic Underpinnings

Abstract

Nitric oxide (NO) and hydrogen sulfide (H₂S) are the key gasotransmitters with an imperious role in the maintenance of cerebrovascular homeostasis. A decline in their levels contributes to endothelial dysfunction that portends ischemic stroke (IS) or cerebral ischemia/reperfusion (CI/R). Nevertheless, their exorbitant production during CI/R is associated with exacerbation of cerebrovascular injury in the post-stroke epoch. NO-producing nitric oxide synthases are implicated in IS pathology and their activity is regulated, inter alia, by various post-translational modifications and chromatin-based mechanisms. These account for heterogeneous alterations in NO production in a disease setting like IS. Interestingly, NO per se has been posited as an endogenous epigenetic modulator. Further, there is compelling evidence for an ingenious crosstalk between NO and H₂S in effecting the canonical (direct) and non-canonical (off-target collateral) functions. In this regard, NO-mediated S-nitrosylation and H₂S-mediated S-sulfhydration of specific reactive thiols in an expanding array of target proteins are the principal modalities mediating the all-pervasive influence of NO and H₂S on cell fate in an ischemic brain. An integrated stress response subsuming unfolded protein response and autophagy to cellular stressors like endoplasmic reticulum stress, in part, is entrenched in such signaling modalities that substantiate the role of NO and H₂S in priming the cells for stress response. The precis presented here provides a comprehension on the multifarious actions of NO and H₂S and their epigenetic underpinnings, their crosstalk in maintenance of cerebrovascular homeostasis, and their "Janus bifrons" effect in IS milieu together with plausible therapeutic implications.

Keywords: Epigenetic; Hydrogen sulfide; Ischemic stroke; Nitric oxide; S-nitrosylation; S-sulfhydration.