Abstract:
:Background Although PAR-1 (protease-activated receptor-1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR-1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR-1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin-angiotensin system activation using renin-overexpressing hypertensive (Ren-Tg) mice. Methods and Results We treated 12- to 16-week-old male wild-type (WT) mice and Ren-Tg mice with continuous subcutaneous infusion of the PAR-1 antagonist SCH79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren-Tg mice than in WT mice, and SCH79797 treatment significantly decreased these thicknesses in Ren-Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren-Tg mice than in WT mice, and both conditions were attenuated by SCH79797 treatment. Cardiac mRNA expression levels of PAR-1, TNF-α (tumor necrosis factor-α), TGF-β1 (transforming growth factor-β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β-myosin heavy chain (β-MHC) to α-MHC were all greater in Ren-Tg mice than in WT mice; SCH79797 treatment attenuated these increases in Ren-Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren-Tg mice than in WT mice, and both conditions were unaffected by SCH79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation, and SCH79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR-1, TGF-β1, and COL3A1 were enhanced by factor Xa, and all were inhibited by SCH79797. Conclusions The results indicate that PAR-1 signaling is involved in cardiac remodeling induced by renin-angiotensin system activation, which may provide a novel therapeutic target for heart failure.
journal_name
J Am Heart Assocjournal_title
Journal of the American Heart Associationauthors
Yokono Y,Hanada K,Narita M,Tatara Y,Kawamura Y,Miura N,Kitayama K,Nakata M,Nozaka M,Kato T,Kudo N,Tsushima M,Toyama Y,Itoh K,Tomita Hdoi
10.1161/JAHA.119.015616subject
Has Abstractpub_date
2020-06-16 00:00:00pages
e015616issue
12issn
2047-9980journal_volume
9pub_type
杂志文章abstract:BACKGROUND:Metformin use reduces the incidence and severity of stroke in patients with type 2 diabetes mellitus (DM). The benefits of metformin for stroke have not been examined in hemodialysis patients with DM. METHODS AND RESULTS:Using the National Health Insurance Research Database, we identified 17 760 patients wi...
journal_title:Journal of the American Heart Association
pub_type: 杂志文章,多中心研究
doi:10.1161/JAHA.117.007611
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abstract::Background Catheter ablation is an effective treatment for atrial fibrillation (AF), but high levels of post-procedure inflammation predict adverse clinical events. Ascorbic acid (AA) has shown promise in reducing inflammation but is untested in this population. We sought to test the feasibility, safety, and prelimina...
journal_title:Journal of the American Heart Association
pub_type: 杂志文章,随机对照试验
doi:10.1161/JAHA.119.014213
更新日期:2020-02-04 00:00:00
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章,meta分析,评审
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doi:10.1161/JAHA.113.000490
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doi:10.1161/JAHA.119.013744
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journal_title:Journal of the American Heart Association
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章,多中心研究
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doi:10.1161/JAHA.118.010778
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章
doi:10.1161/JAHA.119.012125
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abstract:BACKGROUND:Acute end points of catheter ablation for ventricular tachycardia (VT) remain incompletely defined. The aim of this study is to identify causes for failure in patients with structural heart disease and to assess the relation of this acute outcome to longer-term management and outcomes. METHODS AND RESULTS:F...
journal_title:Journal of the American Heart Association
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doi:10.1161/JAHA.113.000072
更新日期:2013-05-31 00:00:00
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章
doi:10.1161/JAHA.120.017970
更新日期:2020-09-15 00:00:00
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journal_title:Journal of the American Heart Association
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doi:10.1161/JAHA.119.014582
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章
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更新日期:2015-01-07 00:00:00
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doi:10.1161/JAHA.118.009098
更新日期:2018-11-06 00:00:00
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journal_title:Journal of the American Heart Association
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更新日期:2020-09-01 00:00:00
abstract::Background To assess differences in platelet inhibition during ticagrelor monotherapy (TIC) or dual therapy with ticagrelor and aspirin (TIC+ASP) in patients after percutaneous coronary intervention using a comprehensive panel of functional tests. Methods and Results In a single-center parallel group, open label, rand...
journal_title:Journal of the American Heart Association
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doi:10.1161/JAHA.120.016495
更新日期:2020-12-15 00:00:00
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journal_title:Journal of the American Heart Association
pub_type: 杂志文章,多中心研究
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更新日期:2017-10-31 00:00:00
abstract::Background Hospitals in the United States vary in their use of intensive care units (ICUs) for hemodynamically stable patients with non-ST-segment-elevation myocardial infarction (NSTEMI). The association between ICU use and long-term outcomes after NSTEMI is unknown. Methods and Results Using data from the National C...
journal_title:Journal of the American Heart Association
pub_type: 杂志文章
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更新日期:2020-03-17 00:00:00