S100a8/a9 Released by CD11b+Gr1+Neutrophils Activates Cardiac Fibroblasts to Initiate Angiotensin II–Induced Cardiac Inflammation and Injury

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Abstract
Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b+Gr1+neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. Immunostaining showed that S100a8/a9 was primarily present in infiltrating CD11b+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 neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.

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