In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
Abstract:
Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease process. Localized hypoxic-induced aortic smooth muscle cell (SMC) apoptosis, a factor amenable to medical intervention, has been reported to participate in the pathogenesis of ascending aortic aneurysm formation (ASAA. β-adrenergic blockers are the drugs most commonly used in the treatment of ASAA. The aim of this study was to investigate the effects of the new third-generation β-blocker nebivolol (NB) on hypoxic-induced smooth muscle cell apoptosis and to characterize the mechanisms activated in this NB action. Treatment of cultured rat thoracic aortic SMC, with NB (10 μM) compared to diluent (100 μM Ascorbic acid) (AA) for 1 hr attenuated hypoxic (5%C02/95%N2) apoptosis as measured by decreases in TUNEL positive staining (15.3+2.3 (AA) vs 5.6+1.2 (NB) % apoptotic nuclei, p 〈 0.05), caspase-3 activity (91.3+2.4 (AA) vs 72.1+0.8 (NB) μmol/mL, p 〈 0.05), the apoptotic ratio of bax/bcl-2 mRNA expression (1.37+0.14 (AA) vs 0.82+0.11 (NB) fold-change, p 〈 0.05), pro-apoptotic miR1 (2.9+0.35 (AA) vs 1.18+0.22 (NB) fold change, p 〈 0.05), and increased anti-apoptotic miR133A (0.74+0.17 (AA) vs 2.3+0.42 (NB) fold change, p 〈 0.05), n=8-10/group. The NB-induced decrease in hypoxic SMC apoptosis was associated with a 5.5 fold increase in nitric oxide (NO) production as quantified by the ratio of Nitrate/Nitrite, a 2.5-3.2 fold increase in Hsp70 mRNA and protein as measured by RT-PCR and Western analysis respectively, and an attenuation of p53 phosphorylation. Blockade of NO production by L-NAME, or siRNA HSP70 knock down, resulted in an increase in p53 phosphorylation and prevented the NB-induced antiapoptotic response of hypoxic SMC. The beneficial pro-survival response of NB in hypoxic thoracic aortic SMCs makes this novel β-blocker clinically relevant in the treatment of ASAA.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.34.suppl_1.119
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1494427-3
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