Induction of Glutathione Synthesis Provides Cardioprotection Regulating NO, AMPK and PPARa Signaling in Ischemic Rat Hearts

Autor:	Volodymyr V. Balatskyi, Yulia V. Goshovska, Vadym F. Sagach, O. O. Piven, Pawel Dobrzyn, Raisa Fedichkina
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	AMPK medicine.medical_specialty Antioxidant SERCA medicine.medical_treatment Science Ischemia Oxidative phosphorylation ischemia heart PPARα Article General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Internal medicine medicine glutathione Ecology Evolution Behavior and Systematics Cardioprotection Paleontology Glutathione medicine.disease Endocrinology chemistry nervous system Space and Planetary Science Anaerobic glycolysis cardioprotection
Zdroj:	Life Volume 11 Issue 7 Life, Vol 11, Iss 631, p 631 (2021)
ISSN:	2075-1729
DOI:	10.3390/life11070631
Popis:	Glutathione (GSH) is essential for antioxidant defence, and its depletion is associated with tissue damage during cardiac ischemia-reperfusion (I/R). GSH is synthesized by the glutamate-cysteine ligase enzyme (GCL) from L-cysteine, which alternatively might be used for hydrogen sulfide production by cystathionine-gamma-lyase (CSE). Here, we have investigated whether in vivo treatment with L-cysteine and an inhibitor of CSE,D,L-propargylglycine (PAG), can modulate cardiac glutathione and whether this treatment can influence heart resistance to I/R in a Langendorff isolated rat hearts model. Pretreatment with PAG + L-cysteine manifested in pronounced cardioprotection, as there was complete recovery of contractile function preserved constitutive NOS activity and limited the production of reactive oxygen and nitrogen species in the ischemized myocardium. Cardiac GSH and GSSG levels were increased by 3.5- and 2.1-fold in PAG + L-cysteine hearts and were 3.3- and 3.6-fold higher in PAG + L-cysteine + I/R compared to I/R heart. The cardioprotective effect of PAG + L-cysteine was completely abolished by an inhibitor of GCL, DL-buthionine-(S,R)-sulfoximine. Further analysis indicated diminished fatty acid β-oxidation, increased glucose consumption and anaerobic glycolysis, and promoted OXPHOS proteins and SERCA2 in PAG + L-cysteine + I/R compared to the I/R group. PAG + L-cysteine inhibited PPARα and up-regulated AMPK signalling in the heart. Thus, induction of glutathione synthesis provided cardioprotection regulating NO, AMPK and PPARa signaling in ischemic rat hearts.
Databáze:	OpenAIRE
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