Moderate Hydrogen Peroxide Postconditioning Ameliorates Ischemia/Reperfusion Injury in Cardiomyocytes via STAT3-Induced Calcium, ROS, and ATP Homeostasis

Abstract

<b><i>Introduction:</i></b> Moderate hydrogen peroxide postconditioning (H<sub>2</sub>O<sub>2</sub>PoC) activates signal transducer and activator of transcription 3 (STAT3) to alleviate mitochondrial calcium overload during cardiac ischemia/reperfusion (I/R). However, the initial time window of STAT3-induced calcium hemostasis, the production of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in H<sub>2</sub>O<sub>2</sub>PoC, and its regulated mechanism remain unknown. This study aimed to investigate H<sub>2</sub>O<sub>2</sub>PoC-induced homeostasis of calcium, ROS and ATP, and the role of STAT3 in the regulation. <b><i>Methods:</i></b> Isolated rat cardiomyocytes were exposed to H<sub>2</sub>O<sub>2</sub>PoC and Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 during I/R. Ca<sup>2+</sup> transients, cell contraction, intracellular calcium concentration, ROS production, ATP contents, phosphorylation of STAT3, gene and protein expression of manganese superoxide dismutase (MnSOD), metallothionein 1 (MT1) and metallothionein 2 (MT2), as well as activities of mitochondrial complex I and complex II were detected. <b><i>Results:</i></b> Moderate H<sub>2</sub>O<sub>2</sub>PoC improved post-ischemic Ca<sup>2+</sup> transients and cell contraction recovery as well as alleviated cytosolic and mitochondrial calcium overload, which were abrogated by AG490 in rat cardiomyocytes. Moderate H<sub>2</sub>O<sub>2</sub>PoC increased ROS production and rate of ROS production at early reperfusion in rat I/R cardiomyocytes, and this phenomenon was also abrogated by AG490. Notably, the expression of phosphorylated nuclear STAT3; gene and protein expression of MnSOD, MT1, and MT2; and activities of mitochondrial complex I and complex II were upregulated by moderate H<sub>2</sub>O<sub>2</sub>PoC but downregulated by AG490. <b><i>Conclusion:</i></b> These findings indicated that the cardioprotection of moderate H<sub>2</sub>O<sub>2</sub>PoC against cardiac I/R could be associated with activated STAT3 at early reperfusion to maintain calcium, ROS, and ATP homeostasis in rat cardiomyocytes.

Gallic Acid Improves Comorbid Chronic Pain and Depression Behaviors by Inhibiting P2X7 Receptor-Mediated Ferroptosis in the Spinal Cord of Rats

“…STAT3 activation is associated with the maintenance of ROS homeostasis . STAT3 is involved in a variety of cellular activities as a transcription factor and plays a nontranscriptional role in mitochondrial metabolism.…”

COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein

“…SOCS3 is a well-known negative regulator of the Janus kinases-signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway, 25 which has been reported to be activated to induce inflammatory responses and be involved in various diseases, such as cerebral I/R injury, myocardial cerebral I/R injury, and inflammatory bowel disease. [26][27][28] Through binding tyrosine kinase receptor, primary receptor shared IL-6 receptor subunit gp130 and bindinJAK2, SOCS3 inhibits STAT3 phosphorylation to restrain inflammation. 29 Here, we find that SOCS3 expression is gradually upregulated in microglia during I/R injury, and overexpression of SOCS3 evidently inhibits I/R-induced STAT3 phosphorylation and inflammatory factor expression, further suggesting SOCS3 functions protective effects in brain inflammation.…”