title: Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension.
abstract: Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism.
  
  
  
  Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured.
  
  
  
  Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIα (CaMKIIα), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIα and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIα.
  
  
  
  These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIα/protein kinase D1/HDAC4/GATA6 pathway.
authors: aHeart Research Center of Chonnam National University Hospital bDepartment of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea cJilin Hospital Affiliated with Jilin University, Jilin, China *Gwi Ran Kim, Soo-Na Cho, and Hyung-Seok Kim contributed equally to the writing of this article.
authors: Gwi Ran
authors: GR
authors: Kim
authors: Soo-Na
authors: SN
authors: Cho
authors: Hyung-Seok
authors: HS
authors: Kim
authors: Seon Young
authors: SY
authors: Yu
authors: Sin Young
authors: SY
authors: Choi
authors: Yuhee
authors: Y
authors: Ryu
authors: Ming Quan
authors: MQ
authors: Lin
authors: Li
authors: L
authors: Jin
authors: Hae Jin
authors: HJ
authors: Kee
authors: Myung Ho
authors: MH
authors: Jeong
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D006984:Hypertrophy; D007668:Kidney / Q000098:blood supply; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D018797:Cell Cycle Proteins; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C577554:MC1568; D011758:Pyrroles; D012097:Repressor Proteins; D000804:Angiotensin II; D004247:DNA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C400300:HDAC4 protein, human; D006655:Histone Deacetylases