Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms

Abstract

Background: Myocardial infarction (MI) is a serious cardiovascular disease associated with myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine (Dex), an α2adrenoceptor agonist, has been reported to protect against I/R injury. We examined the cardioprotective effects of Dex on cardiomyocytes under hypoxia/reoxygenation (H/R) conditions and explored the underlying mechanisms. Materials and methods:A H/R model was established to mimic the MI injury. The CCK-8 assay was performed to measure cell viability. Cellular apoptosis was measured using the Annexin V fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining.The levels of interleukin (IL)-1α and tumor necrosis factor (TNF)α, and the activity of lactate dehydrogenase (LDH) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Reactive oxygen species (ROS) were measured using the 2'-7' dichlorofluorescein diacetate (DCFH-DA) staining assay. In addition, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), and caspase-3 were measured using a commercial kit. siRNA was used to silence Bcl-2, catalase, or STAT3. Western blotting was used to measure the change in the levels of proteins. Results: Dex improved the cell viability and inhibited the inflammatory response in H9c2 cells exposed to H/R treatment. In addition, Dex inhibited apoptosis and alleviated the endoplasmic reticulum (ER) stress and oxidative stress in H9c2 cells under the H/R treatment. Mechanism investigation showed that Dex inhibited the intrinsic pathway of apoptosis. Moreover, Dex enhanced the activation of the JAK2/ STAT3 signaling pathway in H/R-treated H9c2 cells. Conclusion: Altogether, our findings suggested Dex as a promising therapeutic agent for myocardial I/R.

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

“…DEX regulates STAT1 and STAT5 in other diseases, 12,13 while their interaction in myocardial IRI remains unknown. JAK2 might directly participate in the phosphorylation of STAT3 by DEX, 36 which still warrants further investigation. Second,…”

“…DEX regulates STAT1 and STAT5 in other diseases, 12,13 while their interaction in myocardial IRI remains unknown. JAK2 might directly participate in the phosphorylation of STAT3 by DEX, 36 which still warrants further investigation. Second, PI3K-Akt pathway, an essential component of RISK pathway, is significantly enriched in our KEGG analysis (Supplemental Digital Content 2, Figure 1D, http://links.lww.com/AA/E320).…”

“…11 Ser727-phosphorylated STAT3 is known to bind to respiratory chain complexes and promote ATP synthesis, 33 reduce ROS production and maintain redox homeostasis, 34 and inhibit calcium overload 35 and the opening of mitochondrial permeability transition pores (mPTPs). 11 It is previously shown that DEX activated the JAK2/STAT3 pathway in H9C2 cells, 36 but the exact phosphorylation site of STAT3 was not illustrated. Nevertheless, by using the α2-AR antagonist YOH and the STAT3-specific inhibitor Stattic, our current results demonstrated that DEX enhanced STAT3 phosphorylation at Tyr705 and Ser727 in vivo and in vitro, resulting in reduced inflammation, ROS accumulation, calcium overload, and cell apoptosis.…”

Protocatechualdehyde Rescues Oxygen-Glucose Deprivation/Reoxygenation-Induced Endothelial Cells Injury by Inducing Autophagy and Inhibiting Apoptosis via Regulation of SIRT1

“…Bcl-2 acts as an anti-apoptotic gene, overexpression of Bcl-2 has been reported to prevent cerebral ischemic damage ( Zhao et al, 2003 ), and the ratio of BAX/Bcl-2 is of great significance in determining apoptosis ( Wu et al, 2022 ). It has also been shown that excessive accumulation of ROS and reduction of SOD can also cause apoptosis ( Cai et al, 2021 ). Previous studies have found that OGD/R-induced injury can trigger apoptosis ( Cao et al, 2018 ), which is consistent with our results.…”

“…Previous studies have demonstrated that P53 is involved in neuronal death that occurs following ischemia ( Endo et al, 2006 ). Increased expression of P53 is often accompanied by apoptosis ( Cai et al, 2021 ), and autophagy can block the induction of apoptosis by inhibiting the activation of P53 and caspases ( Thorburn, 2008 ; White, 2016 ). Together, these lines of evidence suggest that P53 is involved in the regulation of autophagy and apoptosis, as confirmed by the increased expression of P53 following OGD/R-induced injury in this study.…”