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Inhibition of platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis.

Abstract：

PURPOSE:Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopidogrel could inhibit hypertension-induced cardiac inflammation and fibrosis. METHODS:Using a mouse model of angiotensin II (Ang II) infusion (1,500 ng/[kg·min] for 7 days), we determined the role of platelet activation in Ang II infusion-induced cardiac inflammation and fibrosis using a P2Y12 receptor inhibitor, clopidogrel (50 mg/[kg·day]). RESULTS:CD41 staining showed that platelets accumulated in Ang II-infused hearts. Clopidogrel treatment inhibited Ang II infusion-induced accumulation of α-SMA(+) myofibroblasts and cardiac fibrosis (4.17 ± 1.26 vs. 1.46 ± 0.81, p < 0.05). Infiltration of inflammatory cells, including Mac-2(+) macrophages and CD45(+)Ly6G(+) neutrophils (30.38 ± 4.12 vs. 18.7 ± 2.38, p < 0.05), into Ang II-infused hearts was also suppressed by platelet inhibition. Real-time PCR and immunohistochemical staining showed that platelet inhibition significantly decreased the expression of interleukin-1β and transforming growth factor-β. Acute injection of Ang II or PE stimulated platelet activation and platelet-leukocyte conjugation, which were abolished by clopidogrel treatment. CONCLUSION:Thus, inhibition of platelet activation by clopidogrel prevents cardiac inflammation and fibrosis in response to Ang II. Taken together, our results indicate Ang II infusion-induced hypertension stimulated platelet activation and platelet-leukocyte conjugation, which initiated inflammatory responses that contributed to cardiac fibrosis.

journal_name

Cardiovasc Drugs Ther

journal_title

Cardiovascular drugs and therapy

authors

Jia LX,Qi GM,Liu O,Li TT,Yang M,Cui W,Zhang WM,Qi YF,Du J

doi

10.1007/s10557-013-6471-z

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

521-30

issue

eissn

0920-3206

issn

1573-7241

journal_volume

pub_type

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Inhibition of platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis.