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
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • AT-101 The zinc dependent HDACs are classified into four gro

    2022-06-20

    The zinc-dependent HDACs are classified into four groups based on their structure, complex formation, and expression pattern: class I (HDAC1, HDAC2, HDAC3, and HDAC8), class IIa (HDAC4, HDAC5, HDAC7, and HDAC9), class IIb (HDAC6 and HDAC10), and class IV (HDAC11) [16]. We recently reported on a cytosolic member of HDAC class IIb, HDAC6, and its prominent role in AF progression [17]. HDAC6 deacetylates α-tubulin, which causes disruption of microtubule structure, contractile dysfunction and AF progression [17]. However, whether the other HDAC AT-101 are involved in AF progression is unknown. Of the four classes, class I and IIa are well studied regarding their role in pathological gene expression, structural changes and the development of hypertrophy and heart failure [[18], [19], [20], [21]]. Class I HDACs reveal high HDAC activity in cardiomyocytes, but findings on their role in cardiac disease development are conflicting [18]. In recent years, class IIa HDACs, especially HDAC4, HDAC5 and HDAC9, have attracted considerable attention as regulators of transcriptional reprogramming especially in cardiac diseases. Under normal circumstances, class IIa HDACs localize in the nucleus and suppress cardiomyocyte hypertrophy by repressing the activity of pro-hypertrophic transcription factors, such as members of the myocyte enhancer factor-2 (MEF2) family [19,20]. In response to stress signals, class IIa HDACs are phosphorylated and exported from the nucleus, thereby activating transcriptional reprogramming and the induction of hypertrophic gene expression resulting in cardiac disease [[18], [19], [20], [21]]. Although previously findings indicate a role for transcriptional remodeling in AF progression [3], and our previous study revealed a prominent role for the cytosolic member of HDAC class IIb, HDAC6, in AF progression [17], the involvement of class I and class IIa HDACs in AF is still unknown. Therefore, we examined the role of class I and IIa HDACs on contractile function in tachypaced HL-1 cardiomyocytes and Drosophila, followed by exploration of the downstream AT-101 pathway. Experimental findings were confirmed in AF patients. Here, we show that HDAC3 overexpression causes contractile dysfunction in HL-1 cardiomyocytes. Both pharmacological and genetic inhibition of HDAC3 prevents tachypacing-induced contractile dysfunction in experimental models for AF progression. In contrast, class IIa HDAC5 and HDAC7 overexpression protects against tachypacing-induced contractile dysfunction, possibly via prevention of MEF2 related fetal gene expression, including β-MHC and BNP expression [19,20]. In line, HDAC5 nuclear boosters attenuated tachypacing-induced contractile dysfunction in experimental models for AF. Finally, findings for HDAC3 and HDAC5 were confirmed in atrial tissue biopsies from patients with AF compared to control patients in sinus rhythm (SR), indicating activation of HDAC class I and IIa in patients with AF.
    Materials and methods
    Results
    Discussion In the current study, we evaluated the role of class I and class IIa HDACs in tachypacing-induced cardiomyocyte remodeling. We found that overexpression of class I members, HDAC1 and HDAC3, results in detrimental effects on contractile function in HL-1 cardiomyocytes. Also, HDAC3 expression and activity levels were increased in atrial tissue from PeAF patients compared to controls in SR, indicating a role for HDAC3 in clinical AF. In line, genetic and pharmacological inhibition of HDAC3 protected against tachypacing-induced contractile dysfunction in both HL-1 cardiomyocytes and Drosophila, suggesting that HDAC3 inhibition protects against AF remodeling. In contrast, overexpression of class IIa HDAC5 and HDAC7 revealed protective effects against tachypacing-induced contractile dysfunction via binding to MEF2, thereby possibly preventing fetal gene expression. In addition, tachypacing resulted in phosphorylation of HDAC5, nuclear export and downstream fetal gene activation in HL-1 cardiomyocytes. The experimental findings were confirmed in atrial appendages of patients with PeAF. In line, compounds which boost nuclear HDAC5 attenuated tachypacing-induced contractile dysfunction in both HL-1 cardiomyocytes and Drosophila.