Abstract:
:The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT1-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Werner F,Kojonazarov B,Gaßner B,Abeßer M,Schuh K,Völker K,Baba HA,Dahal BK,Schermuly RT,Kuhn Mdoi
10.1007/s00395-016-0541-xsubject
Has Abstractpub_date
2016-03-01 00:00:00pages
22issue
2eissn
0300-8428issn
1435-1803pii
10.1007/s00395-016-0541-xjournal_volume
111pub_type
杂志文章abstract::It was previously reported that inhibition of carnitine synthesis by 3-(2,2,2-trimethyl-hydrazinium) propionate (MET-88) restores left ventricular (LV) systolic and diastolic function in rats with myocardial infarction (MI). Preservation of the calcium uptake function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) is ...
journal_title:Basic research in cardiology
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journal_title:Basic research in cardiology
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doi:10.1007/978-3-642-72497-8_2
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journal_title:Basic research in cardiology
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doi:10.1007/s00395-009-0047-x
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journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF02005340
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journal_title:Basic research in cardiology
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pub_type: 临床试验,杂志文章,随机对照试验
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pub_type: 杂志文章,评审
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