Inhibition of Platelet Activation by Clopidogrel Prevents Hypertension-Induced Cardiac Inflammation and Fibrosis

Abstract

PurposePlatelets 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.MethodsUsing 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]).ResultsCD41 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.ConclusionThus, 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.

Hypertension, Platelets, and Inflammatory Responses

“…Thus in selected patients with adrenocortical-induced hypertension, clopidogrel therapy may have a dual role, both as a novel blood pressure reducing agent, besides also being an antiplatelet agent, thus indirectly also countering coronary heart disease. That would a major practical application of the basic work reported by Jia et al [1].…”

“…These are diuretics that often indirectly stimulate A-II activity [5], or by calcium channel blockers (CCBs) that have no known effect on A-II, or by an ACEI or ARB. There is thus an important distinction between hypertension as known to clinicians and A-II induced hypertension as newly described by these basic workers [1,2]. It is in patients with primary aldosteronism that increased oxidative stress is reported [6].…”

“…The exciting new basic studies reported in this journal show that A-II blocking agents can be expected to have an effect on the inflammatory responses mediated by platelets, with ultimate inhibition of AII-induced hypertension by the antiplatelet agent clopidogrel [1,2].…”

“…From the point of view of clinical therapy of hypertension, the group of agents that might have anti-inflammatory effects are the ACEIs and ARBs which are ranked equally with diuretics that often increase inflammatory markers [12], while calcium channel blockers (CCBs) have no known anti-inflammatory effects. Nonetheless, there is a relevant potential clinical application of the basic science study by Jia et al [1]. Their studies lead to the suggestion that clopidogrel might influence clinical hypertension [1].…”

“…Nonetheless, there is a relevant potential clinical application of the basic science study by Jia et al [1]. Their studies lead to the suggestion that clopidogrel might influence clinical hypertension [1]. Thus in selected patients with adrenocortical-induced hypertension, clopidogrel therapy may have a dual role, both as a novel blood pressure reducing agent, besides also being an antiplatelet agent, thus indirectly also countering coronary heart disease.…”