Novel GSK-3β Inhibitor Neopetroside A Protects Against Murine Myocardial Ischemia/Reperfusion Injury

Hyoung Kyu Kim; Min Kim; Jubert C Marquez; Seung Hun Jeong; Tae Hee Ko; Yeon Hee Noh; Pham Trong Kha; Ha Min Choi; Dong Hyun Kim; Jong Tae Kim; Young Il Yang; Kyung Soo Ko; Byoung Doo Rhee; Larisa K Shubina; Tatyana N Makarieva; Dmitry Y Yashunsky; Alexey G Gerbst; Nikolay E Nifantiev; Valentin A Stonik; Jin Han

doi:10.1016/j.jacbts.2022.05.004

Novel GSK-3β Inhibitor Neopetroside A Protects Against Murine Myocardial Ischemia/Reperfusion Injury

JACC Basic Transl Sci. 2022 Sep 28;7(11):1102-1116. doi: 10.1016/j.jacbts.2022.05.004. eCollection 2022 Nov.

Authors

Hyoung Kyu Kim^{1

2}, Min Kim^{1

3}, Jubert C Marquez^{1

2}, Seung Hun Jeong^{1

3}, Tae Hee Ko^{1

3}, Yeon Hee Noh^{1

3}, Pham Trong Kha^{1

3}, Ha Min Choi^{1

3}, Dong Hyun Kim⁴, Jong Tae Kim⁵, Young Il Yang⁵, Kyung Soo Ko^{1

2}, Byoung Doo Rhee^{1

2}, Larisa K Shubina⁶, Tatyana N Makarieva⁶, Dmitry Y Yashunsky⁷, Alexey G Gerbst⁷, Nikolay E Nifantiev⁷, Valentin A Stonik⁶, Jin Han^{1

2

3}

Affiliations

¹ Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea.
² Department of Health Sciences and Technology, Graduate School, Inje University, Busan, South Korea.
³ Department of Physiology, BK Plus Project Team, College of Medicine, Inje University, Busan, South Korea.
⁴ Department of Pharmacology and Pharmaco-Genomics Research Center, College of Medicine, Inje University, Busan, South Korea.
⁵ Paik Institute for Clinical Research, Inje University College of Medicine, Busan, South Korea.
⁶ G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok, Russia.
⁷ Laboratory of Glycoconjugate Chemistry, N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia.

Abstract

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2-related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

Keywords: ATP, adenosine triphosphate; GSK-3, glycogen synthase kinase–3; GSK-3β inhibition; I/R, ischemia/reperfusion; MI, myocardial infarction; NAD+, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide, reduced; NPS A; NPS A, neopetroside A; Nqo1, NAD(P)H:quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2–related factor 2; OCR, oxygen consumption rate; ischemia/reperfusion injury; mPTP, mitochondrial permeability transition pore; mTOR, mammalian target of rapamycin; marine pyridine α-nucleoside; mitochondria.