Dexmedetomidine attenuates hypoxia‐induced cardiomyocyte injury by promoting telomere/telomerase activity: Possible involvement of ERK1/2‐Nrf2 signaling pathway

Abstract

Dexmedetomidine (Dex), an α2‐adrenergic receptor (α2‐AR) agonist, possesses cardioprotection against ischemic/hypoxic injury, but the exact mechanism is not fully elucidated. Since telomere/telomerase dysfunction is involved in myocardial ischemic damage, the present study aimed to investigate whether Dex ameliorates cobalt chloride (CoCl2; a hypoxia mimic agent in vitro)‐induced the damage of H9c2 cardiomyocytes by improving telomere/telomerase dysfunction and further explored the underlying mechanism focusing on extracellular signal‐regulated kinase (ERK1/2)‐NF‐E2‐related factor 2 (Nrf2) signaling pathway. The result showed that Dex increased cell viability, decreased apoptosis, and reduced cardiomyocyte hypertrophy as illustrated by the decreases in cell surface area and the biomarker levels for cardiac hypertrophy including atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain β messenger RNA (mRNA) and protein in CoCl2‐exposed H9c2 cells. Intriguingly, Dex increased the telomere length and telomerase activity as well as telomere reverse transcriptase protein and mRNA levels in H9c2 cells exposed to CoCl2, indicating that Dex promotes telomere/telomerase function under hypoxia. In addition, Dex remarkably diminished the reactive oxygen species generation, reduced malondialdehyde content, and increased antioxidative signaling as evidenced by the increases in superoxide dismutase and plasma glutathione peroxidase activities. Furthermore, Dex increased the ratio of P‐ERK1/2/T‐ERK1/2 and P‐Nrf2/T‐Nrf2 and enhanced Nrf2 nuclear translocation in CoCl2‐subjected H9c2 cells, suggesting that Dex promotes the activation of the ERK1/2‐Nrf2 signaling pathway. These novel findings indicated that Dex attenuates myocardial ischemic damage and reduces myocardial hypertrophy by promoting telomere/telomerase function, which may be associated with the activation of the ERK1/2‐Nrf2 signaling pathway in vitro.

Hypoxia-Induced Cardiomyocyte Apoptosis Exacerbates Cardiomyocyte Hypertrophy and Myocardial Injury through p38 MAPK Pathway in SD Rats

“…The mechanisms of right ventricular remodeling and failure are complex, pathological features with cardiomyocyte hypertrophy and myocardial injury, and those mechanisms remain unclear. It`s reported that inflammation is pathogenic in PH, and Nrf2 or ERK1/2-Nrf2 signaling pathway may be a target to prevent or reverse PH [23,24]. CD38 inhibits SIRT3 expression and activates of Ca 2+ -NFAT, playing an essential role in cardiac hypertrophy [25].…”

Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway

“…PKC phosphorylated Nrf2 and activated its detachment from Keap1. ERK1/2 has also been reported to have mediated the antioxidative effect of DEX by participating in Nrf2 activation and translocation into the nucleus ( 56 ). In addition to the two aforementioned kinases, the MAPK signaling pathway ( 57 ) and certain microRNAs (miRNAs), such as miRNA (miR)-27a, miR-153, miR142-5p and miR-144 ( 58 ), have also been reported to have mediated the regulation of Nrf2 expression and its activation.…”

Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy

“…5 attenuates IR-induced ICM through inhibiting ferroptosis by decreasing the production of LPO, increasing the Nrf2 and GPX4 protein, while decreasing the mRNA levels of Ptgs2 and Acsl4 , and the protein levels of ACSL4 ( Lin et al, 2021 ). Dexmedetomidine (6) , a highly selective alpha2-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, posess the protective effect against I/R ( Xiao Z. et al, 2021 ; Chen Y. et al, 2021 ; Deng et al, 2022 ; Yang et al, 2022 ; Hu et al, 2023 ) and H/R ( Wu W. et al, 2022 ; Wang L. et al, 2022 ) induced cardiomyocyte injury. 6 attenuates ICM through inhibiting ferroptosis by activating AMPK/GSK-3β-dependant Nrf2/SLC7A11/GPX4 ( Wang et al, 2022d ).…”