title: Simultaneous treatment with azelnidipine and olmesartan inhibits apoptosis of Hl-1 cardiac myocytes expressing E334k cMyBPC.
abstract: BACKGROUND
  Apoptosis appears to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM). We have previously reported 3 HCM patients carrying the E334K MYBPC3, and that heterologous expression of E334K cMyBPC in cultured cells induced apoptosis. The purpose of this study was to identify pharmacological agents that would inhibit apoptosis in HL-1 cardiomyocytes expressing E334K cMyBPC.
  
  
  RESULTS
  E334K cMyBPC expression in cells increased levels of pro-apoptosis (p53, Bax and cytochrome c) and decreased levels of anti-apoptosis (Bcl-2 and Bcl-XL). While the beta blocker carvedilol (1 μM) normalized the level of p53 and Bcl-2 and the calcium channel blocker (CCB) bepridil (0.5 μM) normalized that of Bcl-2, both the CCB azelnidipine (1 μM) and the angiotensin receptor blocker (ARB) olmesartan (10 μM) normalized those of p53, Bax, cytochrome c, and Bcl-XL. Among those proteins, cytochrome c was the one which showed the highest degree of change. Both azelnidipine (0.1 μM) and olmesartan (1 μM) reduced the level of cytochrome c by 40.2 ± 4.3% and 31.3 ± 5.1%, respectively. The CCB amlodipine and the ARB valsartan reduced it only by 19.1 ± 2.1% and 20.1 ± 5.2%, respectively. Flow cytometric analysis and annexin V staining showed that treatment of cells with azelnidipine (0.1 μM) plus olmesartan (0.3 μM) or that with amlodipine (0.1 μM) plus valsartan (0.3 μM) reduced the number of apoptotic cells by 35.8 ± 10.5% and 18.4 ± 3.2%, respectively.
  
  
  CONCLUSIONS
  Azelnidipine plus olmesartan or amlodipine plus valsartan inhibited apoptosis of HL-1 cells expressing E334K cMyBPC, and the former combination was more effective than the latter.
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Japan.
authors.forename: U
authors.initials: U
authors.lastname: Bahrudin
authors.forename: N
authors.initials: N
authors.lastname: Ikeda
authors.forename: S B
authors.initials: SB
authors.lastname: Utami
authors.forename: N
authors.initials: N
authors.lastname: Maharani
authors.forename: K
authors.initials: K
authors.lastname: Morikawa
authors.forename: P
authors.initials: P
authors.lastname: Li
authors.forename: M A
authors.initials: MA
authors.lastname: Sobirin
authors.forename: A
authors.initials: A
authors.lastname: Hasegawa
authors.forename: S
authors.initials: S
authors.lastname: Sakata
authors.forename: R
authors.initials: R
authors.lastname: Endo
authors.forename: S
authors.initials: S
authors.lastname: Rifqi
authors.forename: Y
authors.initials: Y
authors.lastname: Shirayoshi
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Ninomiya
authors.forename: I
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013777:Tetrazoles / Q000494:pharmacology*; D051020:bcl-X Protein / Q000032:analysis; D000099163:Myosin Binding Protein C
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001383:Azetidinecarboxylic Acid; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004095:Dihydropyridines; D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D013777:Tetrazoles; D051020:bcl-X Protein; D000099163:Myosin Binding Protein C; C494812:Bcl2l1 protein, mouse; C437965:olmesartan; C061679:azelnidipine