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

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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.

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Acknowledgements

This work is supported by the Department of Science and Technology (DST) (D.O. No. SR/CSRI/196/2016), India (Grant number SB/EMEQ-257/2013); Department of Biotechnology (BT/PR18168/MED/29/1064/2016), India; University Grants Commission (UGC) (UH/UGC/UPE-2/Interface studies/Research Projects/B1.4; and UH/UPE-2/28/2015)—Universities with Potential for Excellence-Phase II. Thanks to Dr. Kranthi Varala for helpful suggestions. Parimala Narne is a recipient of Dr. D. S. Kothari Post-Doctoral Fellowship from UGC, India (No. F.4-2/2006(BSR)/13-14/0168). Vimal Pandey acknowledges DST for DST-WOS-A grant (SR/WOS-A/LS-1035/2014(G)).

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  1. Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India

    Parimala Narne, Vimal Pandey & Prakash Babu Phanithi

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Narne, P., Pandey, V. & Phanithi, P.B. Role of Nitric Oxide and Hydrogen Sulfide in Ischemic Stroke and the Emergent Epigenetic Underpinnings. Mol Neurobiol 56, 1749–1769 (2019). https://doi.org/10.1007/s12035-018-1141-6

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