Abstract
Severe hypoxia leads to decline in cardiac contractility and induces arrhythmic events in part due to oxidative damage to cardiomyocyte proteins including ion transporters. This results in compromised handling of Ca2+ ions that trigger heart contractile machinery. Here, we demonstrate that thiol-containing compounds such as N-acetylcysteine (NAC), glutathione ethyl ester (et-GSH), oxidized tetraethylglutathione (tet-GSSG), oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO) are capable of reducing negative effects of hypoxia on isolated rat cardiomyocytes. Preincubation of cardiomyocytes with 0.1 mM GSNO, 0.5 mM et-GSH, GSSG, tet-GSSG or with 10 mM NAC allows cells 5-times longer tolerate the hypoxic conditions and elicit regular Ca2+ transients in response to electric pacing. The shape of Ca2+ transients generated in the presence of GSNO, et-GSH and NAC was similar to that observed in normoxic control cardiomyocytes. The leader compound, GSNO, accelerated by 34% the recovery of normal contractile function of isolated rat heart subjected to ischemia-reperfusion. GSNO increased glutathionylation of Na,K-ATPase alpha-2 subunit, the principal ion-transporter of cardiac myocyte sarcolemma, which prevents irreversible oxidation of Na,K-ATPase and regulates its function to support normal Ca2+ ion handling in hypoxic cardiomyocytes. Altogether, GSNO appears effective cardioprotector in hypoxic conditions worth further studies toward its cardiovascular application.
Highlights
Hypoxia of the myocardium is a frequent complication of a numerous pathological conditions, such as coronary heart disease, myocardial infarction, open heart surgery and preservation of an isolated heart
We have found that the incubation of SC1 mouse fibroblasts with thiol-containing compounds, such as N-acetyl cysteine (NAC), the penetrating analog of GSH, oxidized glutathione (GSSG) and nitrosoglutathione (GSNO), induces an increase in glutathionylation of Na, K-ATPase, which results in an increase in cell viability under hypoxic conditions[11]
We used high-speed fluorescent microscopy to assess the dynamics of Ca2+ transients in isolated electrically stimulated cardiomyocytes under normal and hypoxic conditions (Fig. 1)
Summary
Hypoxia of the myocardium is a frequent complication of a numerous pathological conditions, such as coronary heart disease, myocardial infarction, open heart surgery and preservation of an isolated heart. The increase of ROS levels leads to disruption of redox status of the cell and alters normal functioning of ion transporting systems. If the resources of the antioxidant defense system are not sufficient, irreversible oxidation of protein thiol groups leads to disruption of critical cellular functions[8]. Glutathionylation of proteins belonging to ion transporting system leads to significant changes in their functioning, which is considered important for the adaptation of cells to hypoxia[6,7,9]. We have found that the incubation of SC1 mouse fibroblasts with thiol-containing compounds, such as N-acetyl cysteine (NAC), the penetrating analog of GSH (et-GSH), oxidized glutathione (GSSG) and nitrosoglutathione (GSNO), induces an increase in glutathionylation of Na, K-ATPase, which results in an increase in cell viability under hypoxic conditions[11]. The thiol compounds could replenish the pool of glutathione, which can have a positive effect
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