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Gr1+ neutrophils in the heart. The receptor for advanced glycation end products, an S100a8/ a9 receptor, was expressed in cardiac fibroblasts (CFs). Microarray analysis and Bio-Plex protein array showed that treatment of CFs with recombinant S100a8/a9 activated multiple chemokine and cytokines released. Luciferase reporter assay indicated S100a8/a9-activated nuclear factor-κ B pathway in CFs. Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophilproduced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute
Medial degeneration and inflammation are features of abdominal aortic aneurysms (AAAs). However, the early inflammatory event initiating aneurysm formation remains to be identified. Activated platelets release abundant proinflammatory cytokines and are involved in initial inflammation in various vascular diseases. We investigated the role of platelets in progression of AAA in vivo and in vitro. Histological studies of tissues of patients with AAA revealed that the number of platelets was increased in aneurysm sites along with the increased infiltration of T lymphocytes and augmented angiogenesis. In a murine model of AAA, apolipoprotein E-knockout mice infused with 1,000 ng/kg/min angiotensin II, treatment with clopidogrel, an inhibitor of platelets, significantly suppressed aneurysm formation (47% decrease, P<0.05). The clopidogrel also suppressed changes in aortic expansion, elastic lamina degradation and inflammatory cytokine expression. Moreover, the infiltration of macrophages and production of matrix metalloproteinases (MMPs) were also significantly reduced by clopidogrel treatment. In vitro incubation of macrophages with isolated platelets stimulated MMP activity by 45%. These results demonstrate a critical role for platelets in vascular inflammation and AAA progression.
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