Cardioprotective Effects of Dexmedetomidine in an Oxidative-Stress In Vitro Model of Neonatal Rat Cardiomyocytes

Preterm birth is a risk factor for cardiometabolic disease. The preterm heart before terminal differentiation is in a phase that is crucial for the number and structure of cardiomyocytes in further development, with adverse effects of hypoxic and hyperoxic events. Pharmacological intervention could attenuate the negative effects of oxygen. Dexmedetomidine (DEX) is an alpha 2-adrenoceptor agonist and has been mentioned in connection with cardio-protective benefits. In this study, H9c2 myocytes and primary fetal rat cardiomyocytes (NRCM) were cultured for 24 h under hypoxic condition (5% O-2), corresponding to fetal physioxia (pO(2) 32-45 mmHg), ambient oxygen (21% O-2, pO(2) similar to 150 mmHg), or hyperoxic conditions (80% O-2, pO(2) similar to 300 mmHg). Subsequently, the effects of DEX preconditioning (0.1 & mu;M, 1 mu M, 10 mu M) were analyzed. Modulated oxygen tension reduced both proliferating cardiomyocytes and transcripts (CycD2). High-oxygen tension induced hypertrophy in H9c2 cells. Cell-death-associated transcripts for caspase-dependent apoptosis (Casp3/8) increased, whereas caspase-independent transcripts (AIF) increased in H9c2 cells and decreased in NRCMs. Autophagy-related mediators (Atg5/12) were induced in H9c2 under both oxygen conditions, whereas they were downregulated in NRCMs. DEX preconditioning protected H9c2 and NRCMs from oxidative stress through inhibition of transcription of the oxidative stress marker GCLC, and inhibited the transcription of both the redox-sensitive transcription factors Nrf2 under hyperoxia and Hif1 & alpha; under hypoxia. In addition, DEX normalized the gene expression of Hippo-pathway mediators (YAP1, Tead1, Lats2, Cul7) that exhibited abnormalities due to differential oxygen tensions compared with normoxia, suggesting that DEX modulates the activation of the Hippo pathway. This, in the context of the protective impact of redox-sensitive factors, may provide a possible rationale for the cardio-protective effects of DEX in oxygen-modulated requirements on survival-promoting transcripts of immortalized and fetal cardiomyocytes.

Automated summary

Preterm birth is a risk factor for cardiometabolic disease. Pharmacological intervention using Dexmedetomidine (DEX) can protect cardiomyocytes from oxidative stress. DEX inhibits the transcription of oxidative stress marker GCLC and modulates the activation of the Hippo pathway.