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.


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.