• Xuan Zhang, Feixiang Li, Ji Ma, Xiaobei Zhang, and Yiqing Yin.
• Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
• Shock. 2023 Jan 1; 59 (1): 919891-98.

AbstractIschemic postconditioning (I/Post) reduces I/R injury by activating endogenous cardioprotection mechanisms, such as the JAK/signal transducer and activator of transcription 3 (STAT3) and PI3K/Akt pathways, which offer a traditional approach to myocardial protection. According to a previous study, cardioprotection by I/Post may be lost in aged mice, and in our previous research, hypoxic postconditioning (H/Post) lacked a protective effect in senescent cardiomyocytes, which was associated with low expression of long noncoding RNA H19. The N6-methyladenosine (m 6 A) modification is a dynamic and reversible process that has been confirmed to play a role in cardiovascular diseases. However, the mechanisms of m 6 A modification in myocardial I/Post remain to be explored. Neonatal cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats, and senescence was induced by d -galactose, followed by stimulation of hypoxia-reoxygenation and H/Post. Hypoxic injury was evaluated by cell viability and the Bcl-2/Bax protein ratio. Total m 6 A levels were measured using a colorimetric m 6 A RNA Methylation Quantification Kit, and the m 6 A modified and differentially expressed mRNA was determined by MeRIP (methylated RNA immunoprecipitation). We found that H/Post increased m 6 A methylation and decreased RNA mA demethylase alkB homolog 5 (ALKBH5) expression in aged cardiomyocytes. Furthermore, ALKBH5 knockdown exacerbated injury following H/Post in senescent cardiomyocytes. In addition, ALKBH5 regulated STAT3 expression by mediating its m 6 A modification and long noncoding RNA H19/miR-124-3p. ALKBH5 also alleviated the H/Post injury induced by the low expression of STAT3 in senescent cardiomyocytes.Copyright © 2023 by the Shock Society.

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