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

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-1ß and transforming growth factor-ß. 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.

Association of Left Ventricular Hypertrophy With a Faster Rate of Renal Function Decline in Elderly Patients With Non-End-Stage Renal Disease.

BACKGROUND: Several studies have indicated that chronic kidney disease is independently associated with the presence of left ventricular hypertrophy (LVH). However, little clinical data are currently available regarding the detailed correlation between LVH and renal function in elderly patients with non-end-stage renal disease. METHODS AND RESULTS: A total of 300 in- and outpatients (more than 60 years of age, non-end-stage renal disease), 251 with LVH and 49 without LVH, seen at Beijing Friendship Hospital from January 2000 to December 2010 were included in this retrospective study. One observation period of 12 months was used to detect rapid kidney function decline. The evaluations of cardiac structure and function were performed via echocardiography. The multivariable logistic analysis showed patients with LVH had a much higher risk of rapid kidney function decline than those without LVH. Additionally, the baseline left ventricular mass index was 140 (125-160) g/m(2) in the non-chronic kidney disease group, 152 (130-175) g/m(2) in the mild chronic kidney disease group (estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73 m(2)), and 153 (133-183) g/m(2) in the severe chronic kidney disease group (eGFR<60 ml/min/1.73 m(2)), with a significant difference (P=0.009). CONCLUSIONS: Our data demonstrate that a high rate of renal function decline contributes to pathological LVH in non-end-stage renal disease elderly patients and that LVH is positively associated with renal function decline followed by an increased risk of rapid kidney function decline.

Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy.

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, α-smooth muscle actin, IL-1ß, and TNF-α and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-κB activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5'-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis.