Administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, fibrosis, and hypertrophy.
Does neutralizing S100a9 antibody prevent angiotensin II-induced cardiac inflammation and injury in preclinical models?
Neutrophil-produced S100a8/a9 acts as an initial proinflammatory factor triggering cardiac inflammation and injury during acute hypertension, and its neutralization prevents these effects.
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.
Wu et al. (Tue,) conducted a other in Angiotensin II-induced cardiac inflammation and injury. Neutralizing S100a9 antibody was evaluated on Nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, fibrosis, and hypertrophy. Administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, fibrosis, and hypertrophy.