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  • br Conclusion In this study we investigated functional alter

    2019-12-06


    Conclusion In this study, we investigated functional alterations of ECs following exposure to mechanical and/or physicochemical stimuli. Specifically, hypoxia induced phosphorylation with significant increases after 30 min and the maximum increase was after 180 min. Our data show that a combination of flow shear stress and hyperoxia stimulates eNOS phosphorylation at Ser635, with marked increases after 15 min, significant increases after 30 min, and maximum increases after 60 min. In addition, the maximal phosphorylation levels tended to be greater than after exposures to hypoxia only. On the other hand, under a condition of shear stress and hypoxia, eNOS was phosphorylated at Ser635, but tended to be a smaller degree than after a combination of shear stress and hyperoxia at all time points, suggesting that hyperoxia and shear stress additively contribute the phosphorylation of eNOS at Ser635. The results presented herein have implications for the roles of shear stress and O2 concentration in the phosphorylation of eNOS at Ser635, and contribute to the understanding of eNOS regulatory networks.
    Conflict of interest
    Acknowledgements This research was partially supported by JSPS KAKENHI Grant Number JP16H02529.
    Introduction Epidemiologic studies clearly demonstrate that cardiovascular disease and ischemic introduce disease as its most common type has become a worldwide cause of morbidity and mortality in most countries [1]. Although the process of reperfusion represents the most effective treatment for limiting myocardial infarct size, in itself induce cardiomyocyte death and myocardial injury (Yellon and Hausenloy, 2007). Given that a considerable number of strategies and pharmacological agents only ameliorate the reperfusion damage in experimental conditions, is of vital importance to direct the investigations to find new possible therapies to be applied to humans. The intracellular acidosis occurring during ischemia-reperfusion produces the activation of Na+/H+ exchanger isoform 1 (NHE-1) and HCO3– -dependent transports (BT) which lead to an increase of intracellular Na+ (Vaughan-Jones et al., 2016) and secondarily an increase of intracellular Ca2+ (Bernink et al., 2017). Carbonic anhydrases (CAs), associated to NHE-1 and BT, provide the substrates (H+ and HCO3−) for both transports (Li et al., 2002; Sterling et al., 2002) thus contributing to generation of Ca2+ overload. This increase of Ca2+ is a key event in the cardiomyocyte death occurring after ischemia-reperfusion (Feissner et al., 2002). Therefore, interventions that reduce Ca2+ overload are effective for minimizing the myocardial damage. In this sense, recent data from our laboratory show that CA blockade with benzolamide (BZ) limits the infarct size produced by 30 min of global ischemia and 60 min of reperfusion (Ciocci Pardo et al., 2017). Hearts treated with BZ also exhibit an improvement of post-ischemic myocardial function confirming previous results observed in a model of permanent coronary artery occlusion (Vargas et al., 2016). We also found that p38MAPK-dependent pathways are participating in the beneficial effects observed after BZ treatment (Ciocci Pardo et al., 2017). <br> Materials and methods
    Results Forty minutes of coronary artery occlusion followed by 60 min of reperfusion in rat hearts without any treatment caused an infarct size (IS) of ~35% of the risk area. A significant reduction in IS was obtained when BZ was added to the perfusate (~5%). This beneficial effect was annulled by L-NAME treatment detecting an IS similar to untreated hearts (Fig. 2). At the end of 120 min, non-ischemic hearts exhibited a decrease of contractility of approximately 25%. After 40 min of ischemia and 60 min of reperfusion (IC group) LVDP decreased to approximately 40% of the pre-ischemic value. Fig. 3 shows the beneficial effects of BZ on left ventricular pressure (LVP) at the end of reperfusion period and its attenuation in presence of L-NAME. The mean data indicate that the addition of BZ improved post-ischemic recovery reaching.