Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • br Acknowledgements br Introduction Endothelial cells consti

    2020-10-06


    Acknowledgements
    Introduction Endothelial galunisertib constitute a unique source of humoral factors that may regulate the functions of other cell types via paracrine or endocrine pathways [1]. Among the many molecules originated from the endothelium, nitric oxide (NO) plays versatile roles in maintaining the internal homeostasis. NO promotes relaxation of smooth muscle cells [2], suppresses inflammatory reaction in macrophages and adipose tissue [3], and sensitizes skeletal muscle cells to insulin [4]. In accordance, NO deficiency is associated with an array of human diseases including hypertension, type 2 diabetes, and atherosclerosis [5]. NO is synthesized in the endothelium by endothelial NO synthase (eNOS). Therefore, fluctuations of NO levels under various physiological and pathophysiological conditions reflect the changes in eNOS expression or activity. For instance, eNOS expression is markedly up-regulated in pulmonary vessels right after birth allowing sufficient NO discharge and pulmonary vasodilation [6]. On the other hand, turbulent shear stress, which occurs more frequently at the aortic arch, serves to down-regulate eNOS transcription and promote atherogenesis [7]. Similarly, aging contributes to cardiovascular diseases in part by repressing eNOS transcription [8]. Consistent with this notion, transcription modulators, including KLF2, AP-1, Sp1, and Ets-1, participate in the pathogenesis of human diseases by regulating eNOS expression [9]. We have previously shown that myocardin-related transcription factor A, or MRTF-A, mediates transcriptional repression of eNOS in vascular endothelial cells exposed to oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis [10]. Systemic MRTF-A-null mice are protected from atherosclerosis although it is unknown whether this phenotype is underscored by eNOS normalization in endothelial cells [11]. Interferon gamma (IFN-γ) is a prototypical pro-inflammatory cytokine primarily released by CD4+ Th1 lymphocytes [12]. Usually functioning within the adaptive immune system to safeguard the organism from invading pathogens, excessive IFN-γ production is thought to be associated with cardiovascular diseases [13], metabolic disorders [14], and neurodegenerative diseases [15]. Recently it has been demonstrated that angiotensin II induced hypertension was attenuated in mice with a deficiency in interferon gamma (IFN-γ) [16]. We therefore hypothesized that IFN-γ may contribute to hypertension by influencing eNOS levels in vascular endothelial cells. Our data as summarized here suggest that IFN-γ directly represses eNOS transcription. Class II trans-activator (CIITA) mediates IFN-γ induced eNOS repression by enlisting the histone H3K9 trimethyltransferase SUV39H1. Therefore, targeting the CIITA-SUV39H1 axis may yield novel interventional strategies for vascular endothelial disorders.
    Materials and methods
    Results
    Discussion Alteration of eNOS expression serves as both a biomarker and a potential mechanism underlying a host of cardiovascular diseases [36]. Here we detail a novel epigenetic mechanism underlying the transcriptional regulation of the eNOS gene by the pro-inflammatory cytokine IFN-γ in endothelial cells. Our data demonstrate that class II trans-activator interacts with the histone methyltransferase SUV39H1 to mediate IFN-γ induced eNOS repression (Fig. 6G). CIITA is mostly known as a transcriptional activator for class II major histocompatibility complex (MHC II) genes [37]. Although several genes, including IL-4 [38], cathepsin E [39], IL-10 [40], and collagen type I [28], are transcriptionally repressed by CIITA, the underlying epigenetic mechanisms are not clear. We have previously reported that CIITA mediates IFN-γ induced repression of the SIRT1 gene in skeletal muscle cells [26]. Specifically, CIITA recruits HDAC4, a class II histone deacetylase (HDAC), to remove histone acetylation from the SIRT1 proximal promoter region in response to IFN-γ stimulation [29]. Gan et al have shown that active histone deacetylation taking place surrounding the eNOS promoter region ensures that transcription from the eNOS locus is silenced in non-endothelial cells [41]. Of note, HDAC4 and SUV39H1 can be found in the same complex and coordinately repress gene expression to promote cardiac hypertrophy in mice [42]. Whether HDAC4 may participate in eNOS trans-repression in IFN-γ-treated endothelial cells awaits further scrutiny. In addition, we observed that CIITA binding to the eNOS promoter correlates with the accumulation of H3K9 trimethylation as well as the disappearance of H3K4 trimethylation. Whereas this observation can be potentially explained by the model in which enhanced H3K9 trimethylation following SUV39H1 recruitment antagonizes H3K4 trimethylation, an equally plausible explanation is that CIITA may recruit an H3K4 tri-demethylase to the eNOS promoter. There are at least four known demethylases, termed KDM5A, KDM5B, KDM5C, and KDM5D, with a specificity towards trimethylated H3K4 [43]. Several of these enzymes have been implicated in endothelial function/dysfunction although none have been found to directly regulate eNOS transcription [44,45]. Of interest, SIRT1 has a well-documented role regulating eNOS expression: endothelial-specific SIRT1 transgenic mice exhibit enhanced eNOS expression whereas mice with endothelial-selective SIRT1 deletion are severely compromised in the angiogenic ability following ischemia probably due to a reduction in eNOS expression [46]. Although we provide evidence here to show that CIITA directly binds to the proximal eNOS promoter, it remains an intriguing possibility that CIITA may indirectly regulate eNOS transcription by controlling SIRT1 levels. Clearly, these lingering questions warrant further investigation.