title: Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy.
abstract: 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-1β, 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.
authors.affiliation: Beijing Anzhen Hospital (G.-M.Q., L.-X.J., Y.-L.L., J.D.), The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing 100029, China; and Department of Pathology (H.-H.L.), Capital Medical University, Beijing 100069, China.
authors.forename: Guan-Ming
authors.initials: GM
authors.lastname: Qi
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Jia
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Li
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D052242:Adiponectin / Q000494:pharmacology* / Q000627:therapeutic use; D000804:Angiotensin II; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D052242:Adiponectin; D000804:Angiotensin II