Open AccessAn AT1-Receptor Antagonist and an Angiotensin-Converting Enzyme Inhibitor Protect Against Hypoxia-Induced Apoptosis in Human Aortic Endothelial Cells Through Upregulation of Endothelial Cell Nitric Oxide Synthase Activity
Author(s) -
Naoyuki Matsumoto,
Hiroki Manabe,
Jun Ochiai,
Noriko Fujita,
Tomohisa Takagi,
Manabu Uemura,
Yuji Naito,
Norimasa Yoshida,
Saori Oka,
Toshikazu Yoshikawa
Publication year - 2003
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/01.shk.0000070734.34700.80
Subject(s) - angiotensin ii receptor type 1 , nitric oxide synthase , apoptosis , hypoxia (environmental) , bradykinin , chemistry , dna fragmentation , angiotensin ii , nitric oxide , endothelial stem cell , endocrinology , lactate dehydrogenase , medicine , receptor , biology , programmed cell death , biochemistry , enzyme , organic chemistry , oxygen , in vitro
The protective effects and roles of AT1-receptor antagonists (AT1-RA) or angiotensin-converting enzyme inhibitors (ACEI) on vascular endothelial cell (EC) injury during hypoxia are not entirely known. Therefore, we investigated these effects and mechanisms in human aortic (HA) EC. DNA fragmentation, Lactate dehydrogenase (LDH) release, and caspase-3 activity were measured in cultured HAEC after exposure to hypoxia in the presence or absence of an AT1-RA (candesartan, CS) and/or an ACEI (temocaprilat, TC). Next, we investigated endothelial cell nitric oxide synthase (ecNOS) and inducible (i) NOS to determine the role of the bradykinin(BK)-NO pathway in the protective effect on ACEI and AT1-RA in the setting of hypoxia-induced apoptosis. Exposure to hypoxia increased DNA fragmentation in HAEC associated with the activation of caspase-3, but did not affect LDH release. In addition, hypoxia induced ecNOS mRNA but not mRNA iNOS. CS and/or TC reduced apoptosis induced by hypoxia in a dose-dependent manner, and significantly increased BK and ecNOS expression. This effect was attenuated by the kinin B2 receptor antagonist, HOE 140, and the NOS inhibitor, N-nitro-L-arginine methylester (L-NMMA). Hypoxia activates the pathway leading to apoptosis by enhancing caspase-3 activity. Both CS and TC can ameliorate hypoxia-induced apoptosis in HAEC through inhibiting caspase-3 activation by enhancing ecNOS activity, via the accumulation of BK.