FIsetin Preserves Interfibrillar Mitochondria to Protect Against Myocardial Ischemia-Reperfusion Injury.

Autor: Shanmugam K; Vascular Biology Lab, 117 Anusandhan Kendra, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India.; School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India., Prem PN; Vascular Biology Lab, 117 Anusandhan Kendra, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India., Boovarahan SR; Vascular Biology Lab, 117 Anusandhan Kendra, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India., Sivakumar B; Vascular Biology Lab, 117 Anusandhan Kendra, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India., Kurian GA; Vascular Biology Lab, 117 Anusandhan Kendra, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India. kurian@scbt.sastra.edu.; School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India. kurian@scbt.sastra.edu.
Jazyk: angličtina
Zdroj: Cell biochemistry and biophysics [Cell Biochem Biophys] 2022 Mar; Vol. 80 (1), pp. 123-137. Date of Electronic Publication: 2021 Aug 14.
DOI: 10.1007/s12013-021-01026-4
Abstrakt: According to our previous study, fisetin (3,3',4',7-tetrahydroxyflavone), a bioactive phytochemical (flavonol), reportedly showed cardioprotection against ischemia-reperfusion injury (IRI) by reducing oxidative stress and inhibiting glycogen synthase kinase 3β (GSK3β) [1]. GSK3β is said to exert a non-mitochondrial mediated cardioprotection; therefore, distinct mechanisms of GSK3β on the regulatory effect of mitochondria need to be addressed. The two distinct mitochondrial subpopulations in the heart, namely interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM), respond differently to disease states. The current study aimed to understand the effect of fisetin on the subpopulation-specific preservation of IFM and SSM while rendering cardioprotection against ischemia reperfusion (I/R). Rats were pre-treated with fisetin (20 mg/kg) intraperitoneally, and IRI was induced using Langendorff isolated heart perfusion technique. Hemodynamic parameters were recorded, and the cardiac injury was assessed using infarct size (IS), lactate dehydrogenase (LDH), and creatine kinase (CK) levels. Subpopulation-specific mitochondrial preservation was evaluated by electron transport chain (ETC), catalase, superoxide dismutase (SOD), and glutathione (GSH) activities. The bioavailability of fisetin in IFM and SSM was measured using the fluorescence method. The ability of fisetin to bind directly to the mitochondrial complex-1 and activating it through donating electrons to FMN was studied using molecular docking studies and further validated by in vitro rotenone sensitivity assay. Cardioprotective effects exhibited by fisetin were mainly mediated through IFM preservation. Mitochondrial bioavailability of fisetin is more in IFM than SSM in both ex vivo and in vitro conditions. Fisetin increased mitochondrial ATP production in I/R insult hearts by activating ETC complex 1. Inhibition of complex 1 prevents the ATP-producing capacity of fisetin. Our results provide evidence that fisetin plays a protective role in myocardial IRI, possibly by preserving the functional activities of IFM.
(© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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