Abstract:
BACKGROUND:Data with animal cells and models suggest that thrombin activates cardiac fibroblasts (Fib) to myofibroblasts (myoFib) via protease-activated receptor 1 (PAR1) cleavage, and in this way promotes adverse atrial remodeling and, thereby, atrial fibrillation (AF). OBJECTIVE:Here, we explored the effects of thrombin on human atrial Fib and whether they are antagonized by the clinically available direct thrombin inhibitor, dabigatran. METHODS:Fib isolated from atrial appendages of patients without AF undergoing elective cardiac surgery were evaluated for PAR expression and treated with thrombin with or without dabigatran. PAR1 cleavage, downstream signaling and myoFib markers were investigated by immunofluorescence and Western blot. Collagen synthesis, activity of matrix metalloprotease (MMP)-2 and proliferation were assessed by Picro-Sirius red staining, gelatinolytic zymography and BrdU incorporation, respectively. Fib function was studied as capability to contract a collagen gel and stimulate the chemotaxis of peripheral blood monocytes from healthy volunteers. RESULTS:Primary human atrial Fib expressed PAR1, while levels of the other PARs were very low. Thrombin triggered PAR1 cleavage and phosphorylation of ERK1/2, p38 and Akt, elicited a switch to myoFib enriched for αSMA, fibronectin and type I collagen, and induced paracrine/autocrine transforming growth factor beta-1, cyclooxygenase-2, endothelin-1 and chemokine (C-C motif) ligand 2 (CCL2); conversely, MMP-2 activity decreased. Thrombin-primed cells displayed enhanced proliferation, formed discrete collagen-containing cellular nodules, and stimulated the contraction of a collagen gel. Furthermore, their conditioned medium caused monocytes to migrate. All these effects were prevented by dabigatran. CONCLUSION:These results with human cells complete the knowledge about thrombin actions on cardiac Fib and strengthen the translational potential of the emerging paradigm that pharmacological blockade of thrombin may counteract molecular and cellular events underlying AF.
journal_name
Int J Cardioljournal_title
International journal of cardiologyauthors
Altieri P,Bertolotto M,Fabbi P,Sportelli E,Balbi M,Santini F,Brunelli C,Canepa M,Montecucco F,Ameri Pdoi
10.1016/j.ijcard.2018.05.033subject
Has Abstractpub_date
2018-11-15 00:00:00pages
219-227eissn
0167-5273issn
1874-1754pii
S0167-5273(17)37240-6journal_volume
271pub_type
杂志文章abstract:INTRODUCTION:Whether in patients with acute central sub-massive or non-massive pulmonary embolism, mild troponin I increase (>0.03 mug/L) predicts in-hospital occurrence of hemodynamic instability and death independent to prognostically relevant clinical, laboratory and echocardiographic information is not fully establ...
journal_title:International journal of cardiology
pub_type: 临床试验,杂志文章
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abstract:OBJECTIVES:To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI). BACKGROUND:PAD is associated with poorer prognosis in patients ...
journal_title:International journal of cardiology
pub_type: 杂志文章,meta分析
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journal_title:International journal of cardiology
pub_type: 杂志文章
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journal_title:International journal of cardiology
pub_type: 杂志文章
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
pub_type: 信件,多中心研究
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journal_title:International journal of cardiology
pub_type: 社论
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journal_title:International journal of cardiology
pub_type: 信件
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journal_title:International journal of cardiology
pub_type: 杂志文章
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journal_title:International journal of cardiology
pub_type: 杂志文章
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journal_title:International journal of cardiology
pub_type: 杂志文章,评审
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更新日期:1998-10-01 00:00:00
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journal_title:International journal of cardiology
pub_type: 杂志文章
doi:10.1016/s0167-5273(98)00145-4
更新日期:1998-10-01 00:00:00
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journal_title:International journal of cardiology
pub_type: 杂志文章
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更新日期:2014-10-20 00:00:00
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journal_title:International journal of cardiology
pub_type: 信件
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更新日期:2006-09-20 00:00:00
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pub_type: 杂志文章,随机对照试验
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更新日期:2017-09-15 00:00:00
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journal_title:International journal of cardiology
pub_type: 杂志文章
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pub_type: 杂志文章,随机对照试验
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journal_title:International journal of cardiology
pub_type: 信件
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更新日期:2005-05-25 00:00:00
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更新日期:2018-09-15 00:00:00