title: Inhibition of platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Disease, Capital Medical University, Ministry of Education, Beijing Institutue of Heart Lung & Blood Vessel Disease, Beijing, 100029, China.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Jia
authors.forename: Guan-Ming
authors.initials: GM
authors.lastname: Qi
authors.forename: Ou
authors.initials: O
authors.lastname: Liu
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Zhang
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000077144:Clopidogrel; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control*; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D000077144:Clopidogrel; D013988:Ticlopidine