Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinase II

Wu, Dan; Hu, Qingxun; Tan, Bo; Rose, Peter; Zhu, Deqiu; Zhu, Yi Zhun

Abstract

Aims: Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in the development of heart failure and in the induction of myocardial mitochondrial injury. Recent evidence has shown that hydrogen sulfide (H2S), produced by the enzyme cystathionine γ-lyase (CSE), improves the cardiac function in heart failure. However, the cellular mechanisms for this remain largely unknown. The present study was conducted to determine the functional role of H2S in protecting against mitochondrial dysfunction in heart failure through the inhibition of CaMKII using wild type and CSE knockout mouse models.
Results: Treatment with S-propyl-L-cysteine (SPRC) or sodium hydrosulfide (NaHS), modulators of blood H2S levels, attenuated the development of heart failure in animals, reduced lipid peroxidation, and preserved mitochondrial function. The inhibition CaMKII phosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds. Interestingly, CaMKII activity was found to be elevated in CSE knockout (CSE-/-) mice as compared to wild type animals and the phosphorylation status of CaMKII appeared to relate to the severity of heart failure. Importantly, in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein, however, in CSE-/- mice S-sulfhydration was abolished following SPRC treatment.
Innovation and Conclusions: A novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKII is presented. SPRC mediated S-sulfhydration of CaMKII was found to inhibit CAMKII activity and to preserve cardiovascular homeostasis.

Citation

Wu, D., Hu, Q., Tan, B., Rose, P., Zhu, D., & Zhu, Y. Z. (2018). Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinase II. Redox Biology, 19, 250-262. https://doi.org/10.1016/j.redox.2018.08.008

• Journal Article Type: Article
• Acceptance Date: Aug 17, 2018
• Online Publication Date: Aug 22, 2018
• Publication Date: 2018-10
• Deposit Date: Sep 26, 2018
• Publicly Available Date: Sep 26, 2018
• Journal: Redox Biology
• Print ISSN: 2213-2317
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 19
• Pages: 250-262
• DOI: https://doi.org/10.1016/j.redox.2018.08.008
• Keywords: Hydrogen Sulfide, Mitochondria, Heart Failure, Ca2+/calmodulin-dependent protein kinase II, S-sulfhydration
• Public URL: https://nottingham-repository.worktribe.com/output/1134403
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2213231718305652?via%3Dihub