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    • In addition to the regulation

    2021-11-25

    In addition to the regulation afforded by calcineurin/NFAT axis, it has been shown that deregulation of some microRNAs (e.g. miR-155) can induce activation of Fas/FasL-in various cell types [72]. Furthermore, Fas–FasL interactions appear to be an important mechanism for the maintenance of immune privilege in some human tissue, such as the eye and in the vertebral disk, to induce apoptosis in infiltrating inflammatory cells, which is, in fact, a protective mechanism [73], [74]. However, the effect of hyperglycemia and CO-HFD on such miRNA and the role of Fas/FasL on immune privilege in the heart and vasculature of these rats should be not neglected to reveal a full mechanism of action. However, in spite of these findings, this study has some limitation. The first limitation of this study is that we didn't investigate the role of other NFAT members in the extrinsic apoptotic cell death induced by CO-HFD or hyperglycemia. In fact, we have selected NFAT4 as indicated by other authors to be the most sensitive to hyperglycemia as shown in the vascular smooth muscle, cerebral arteries retina and aorta of animals [23], [24], [75], [76]. In addition, All NFAT members cytoplasmic retention, as well as nuclear import and export, are regulated by other kinases including, GS3Kβ and MAPKs [77], all of which are known to be activated by ROS and Ca2+. Unfortunately, these were not investigated in this study and provide an excellent area for further research. In conclusion, the novel findings of this study indicate that Fas/FasL-mediated cell death observed in diabetic hearts or induced by hyperglycemia, in vitro, is mediated, at least by, activation of Ca+2/NFAT/FasL axis and is potentiating by CO-HFD through their stimulatory effect of expression of Fas.
    Conflict of interest
    Introduction Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It affects all exocrine organs including the airways, pancreas, intestine and sweat glands, however, pulmonary disease causes most of the morbidity and mortality associated with CF [1]. CFTR – a 1480 amino Iberiotoxin protein that functions as a chloride channel – is highly expressed in the airway epithelium where it regulates chloride ion movement [2]. A single deletion of a phenylalanine residue at position 508 in CFTR (ΔF508-CFTR) results in a misfolded protein that is associated with approximately 90% of CF cases [3]. CF lung disease is associated with the failure of pulmonary host defence leading to a vicious cycle of continual infection, inflammation and remodelling of lung tissue. The airway epithelium plays a key role in pulmonary host defence, and apoptosis is a physiological process essential for homeostasis of epithelial function. Apoptosis, or programmed cell death, is a form of regulated cell death in which activation of specific proteases called caspases leads to DNA cleavage and cell death. Previous work suggests that apoptosis is dysfunctional in the CF airways with conflicting results. While some reports describe defective apoptosis of epithelial cells expressing mutant forms of CFTR [[4], [5], [6]], a number of others report excessive apoptosis in CF cells [[7], [8], [9], [10], [11], [12], [13]]. In addition, it is unclear how CFTR misfolding and dysfunction contributes to apoptosis or the susceptibility of cells to pro-apoptotic stimuli. Nonetheless, accumulation of apoptotic cells as evident in the CF lung may precipitate chronic inflammation and progressive airway damage [14,15]. Previous studies have focused on the effect of external stimuli on apoptosis in CF epithelium [8,16]. However, we now show that in basal (unstimulated) CF epithelial cells, indices of apoptosis are increased (caspase-3, caspase-8). Further evaluation of upstream apoptotic factors demonstrated increased expression of Fas which contributed to the increased activation of caspase-3 and -8 demonstrated in these cells. Treatment of CF cells with Fas activating antibody, CH-11, resulted in a significant increase in caspase-3 and -8 activation as well as significant increase in apoptosis in these cells compared to non-CF cells. Increased Fas expression was related to CFTR function as treatment of primary non-CF bronchial epithelial cells with a CFTR inhibitor resulted in increased Fas expression in these cells. These findings indicate that CF epithelium is in a primed condition for apoptosis which results in significant programmed cell death upon activation. These finding may impact on effective innate host defence function offered by the epithelial barrier in the CF lung.