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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 63; no. 6; pp. 1241 - 1250
• Main Authors: Wu, Yina, Li, Yulin, Zhang, Congcong, A, Xi, Wang, Yueli, Cui, Wei, Li, Huihua, Du, Jie
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-06-2014
• Subjects: Angiotensin II - immunology; Angiotensin II - pharmacology; Animals; Animals, Newborn; Antibodies - immunology; Antibodies - pharmacology; Antigens, Ly - immunology; Antigens, Ly - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Calgranulin A - genetics; Calgranulin A - immunology; Calgranulin A - metabolism; Calgranulin B - genetics; Calgranulin B - immunology; Calgranulin B - metabolism; Cardiology. Vascular system; CD11b Antigen - immunology; CD11b Antigen - metabolism; Cells, Cultured; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - metabolism; Hypertension - genetics; Hypertension - immunology; Hypertension - prevention & control; Immunohistochemistry; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - immunology; Myocytes, Cardiac - metabolism; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Oligonucleotide Array Sequence Analysis; Receptor for Advanced Glycation End Products; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Transcriptome - drug effects; Transcriptome - immunology; Heart; Hypertension; S 100 Protein; S100 proteins; Injury; Peptide hormone; Granulocyte; Cardiovascular disease; Inflammation; Trauma; Octapeptide; Renin angiotensin system; Circulatory system; Lesion; Neutrophil; Angiotensin II; Cardiology; Fibroblast; inflammation; hypertension; angiotensin II
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hypertensionaha.113.02843

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.