title: Effects of the novel angiotensin II receptor type I antagonist, fimasartan on myocardial ischemia/reperfusion injury.
abstract: BACKGROUND
  The aim of this study was to investigate the cardioprotective effect of fimasartan, a newly developed angiotensin II receptor type I blocker (ARB), against myocardial ischemia/reperfusion (I/R) injury and to identify the mechanism by which it reduces mitochondrial damage.
  
  
  METHODS
  Fimasartan was administered intravenously to Sprague-Dawley rats (3mg/kg), cardiomyocytes (50 μM), and H9c2 cells (50 μM) before ischemia or hypoxia. Myocardial infarction (MI), echocardiograms, DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling, immunoblotting, oxygen consumption, confocal microscopic appearance, and L-type Ca(2+) current (ICa,L) were then assessed.
  
  
  RESULTS
  Fimasartan pretreatment remarkably reduced the rate of MI and improved cardiac performance well after I/R (n = 9/group). Fimasartan also reduced apoptotic cell death both in vivo and in hypoxia/reoxygenation (H/R)-treated H9c2 cells (n = 5~8/group). H/R-induced mitochondrial O2(-) production and collapse of membrane potential were markedly attenuated in fimasartan-treated cardiomyocytes (n = 4 ~ 6/group). Additionally, mitochondrial Ca(2+) overload during reoxygenation was suppressed by fimasartan (n = 4~6/group), and this was found to be possibly related to the inhibition of ICa,L and mitochondrial Ca(2+) uniporter. Furthermore, fimasartan pretreatment increased phosphorylations of Akt and glycogen synthase kinase-3β (n = 5 ~ 7/group), decreased pro-apoptotic p53 levels, and increased anti-apoptotic Bcl-2 levels (n = 4) during reperfusion.
  
  
  CONCLUSIONS
  Fimasartan preconditioning has the potential to modulate Bcl-2 and suppress I/R-induced Ca(2+) overload by inhibiting ICa,L and MCU. These beneficial effects could prevent the mitochondrial dysfunction and apoptosis accompanied by I/R.
authors: National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
authors: Jin
authors: J
authors: Han
authors: Sung-Ji
authors: SJ
authors: Park
authors: Vu Thi
authors: VT
authors: Thu
authors: Sung-Ryul
authors: SR
authors: Lee
authors: Le Thanh
authors: le T
authors: Long
authors: Hyoung Kyu
authors: HK
authors: Kim
authors: Nari
authors: N
authors: Kim
authors: Seung Woo
authors: SW
authors: Park
authors: Eun-Seok
authors: ES
authors: Jeon
authors: Eun-Ji
authors: EJ
authors: Kim
authors: Chang-Hwan
authors: CH
authors: Yoon
authors: Goo-Young
authors: GY
authors: Cho
authors: Dong-Ju
authors: DJ
authors: Choi
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D001713:Biphenyl Compounds; D011743:Pyrimidines; D013777:Tetrazoles; C558933:fimasartan
keywords: AAR; ADP; ARB; AT(1); ATP; Fimasartan; GSK-3β; H/R; I(Ca,L); I/R; L-type Ca(2+) channel; L-type Ca(2+) current; LAD; LV; MCU; MI; MPTP; Mitochondrial Ca(2+) uniporter; Reperfusion; TMRE; TUNEL; adenosine diphosphate; adenosine triphosphate; angiotensin II receptor blocker; angiotensin II type 1; area at risk; glycogen synthase kinase-3β; hypoxia/reoxygenation; ischemia/reperfusion; left anterior descending coronary artery; left ventricle; mitochondrial Ca(2+) uniporter; mitochondrial permeability transition pore; mitochondrial transmembrane potential; myocardial infarction; terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling; tetramethylrhodamine ethyl ester; ∆Ψm