Dexmedetomidine protects cardiac microvascular endothelial cells from the damage of ogd/r through regulation of the pparδ‐mediated autophagy

Abstract

Background: Dexmedetomidine (Dex) exerts an effective therapeutic role in numerous diseases associated with ischemia/reperfusion (I/R) injury via its anti-apoptosis properties. Therefore, this study explores the cardioprotective effects of Dex in cardiac microvascular endothelial cells (CMECs) in response to oxygen-glucose deprivation and re-oxygenation (OGD/R) injury and its potential mechanism. Material and methods: CMECs were pretreatment with different concentration of Dex, then exposed to OGD/R. Cell viability was measured with CCK-8 assay. Apoptosis was evaluated by flow cytometry, and apoptosis-related protein was determined by Western blot. Autophagy was assessed by transmission electron microscopy and autophagy-related proteins. Besides, the role peroxisome proliferator-activated receptors (PPARδ) in Dex-mediated anti-apoptosis property was validated with agonist and antagonist. Results: OGD/R significantly decreased cell viability, increased reactive oxygen species, caused disorder of autophagy, and increased apoptosis in CMECs. Dex enhanced the viability of the OGD/R-treated CMECs and effectively decreased reactive oxygen species production. Autophagy in CMECs was activated by Dex, as evidenced by the increase in the ratio of LC3B-II/I, expression level of Beclin1 and number of autophagosomes in the OGD/R-induced CMECs. The mechanistic investigation indicated that PPARδ antagonist GW501516 aggravated cell damage following OGD/R, while PPARδ agonist GW6471 partly abolished the Dex-mediated protective effects.Conclusions: Dex activated the PPARδ-AMPK-PGC-1α pathway-mediated autophagy in CMECs, therefore to inhibit excessive apoptosis induced by OGD/R. Dex may potentially be a therapeutic intervention for myocardial I/R injury.

Dexmedetomidine attenuates renal ischemia–reperfusion injury through activating PI3K/Akt‐eNOS signaling via α2 adrenoreceptors in renal microvascular endothelial cells

“…And first, we demonstrate DEX treatment significantly reduces renal I/R injury by activating PI3K/Akt signaling and suppressing inflammation via α 2 ‐AR in renal microvascular endothelial cells. Similarly, one recent study found that DEX protected cardiac microvascular endothelial cells against OGD/R‐induced apoptosis via activating PPARδ‐AMPK‐PGC‐1α signaling 42 . Another previous research indicated that DEX attenuated lung apoptosis induced by renal I/R injury through mediating the α 2 AR/PI3K/Akt pathway 43 .…”

“…Similarly, one recent study found that DEX protected cardiac microvascular endothelial cells against OGD/R-induced apoptosis via activating PPARδ-AMPK-PGC-1α signaling. 42 Another previous research indicated that DEX attenuated lung apoptosis induced by renal I/R injury through mediating the α 2 AR/PI3K/Akt pathway. 43 Therefore, the microvascular endothelial cells might be the key factor for protective effects of DEX in I/R injury.…”

Axonal protection by combination of ripasudil and brimonidine with upregulation of p-AMPK in TNF-induced optic nerve degeneration

“…Very recent studies have also shown a close relationship between ROCK inhibition and AMPK activation in several different cells [ 30 , 31 ], suggesting that ROCK inhibitors may act as upstream effectors of AMPK. On the other hand, the α2-adrenoreceptor agonist dexmedetomidine protected cardiovascular endothelial cells via AMPK-autophagy [ 32 ]. In addition, it was shown that dexmedetomidine exerted neuroprotection via AMPK-autophagy in SH-SY5Y-APP cells [ 33 ].…”

Endothelial Autophagy in Coronary Microvascular Dysfunction and Cardiovascular Disease

“…However, according to Sun's study, the mitophagy induced by the Rcan1-1L (regulator of calcineurin 1-1L) overexpression contributed to cell survival under hypoxic conditions [109]. During an oxygen-glucose deprivation and reoxygenation (OGD/R) injury, Shao et al reported that dexmedetomidine could protect the CMECs by activating the peroxisome proliferator-activated receptors (PPARδ)-AMPK-PGC-1α pathway-dependent autophagy, effectively causing a decrease in ROS production and an increase in cell viability [110]. Nevertheless, inhibited autophagy participated in the beneficial role of polysaccharides from Enteromorpha Prolifera (PEP) in OGD-induced human CMEC injury by promoting the mTOR pathway [111].…”

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cells11132081/s1, Table S1: Mechanistic studies implicating endothelial autophagy or mitophagy in cardiovascular diseases [93,105,106,[108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][130][131][132][133][149][150][151][152][153][154][155][156][157][158][159][160][166][167][168][169][170]181,[184][185][186][187]…”