Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.
Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB-mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms.
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Jun
J
Ren
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Zhenjie
Z
Liu
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Qiwei
Q
Wang
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Jasmine
J
Giles
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Jason
J
Greenberg
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
Nader
N
Sheibani
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.).
K Craig
KC
Kent
Division of Vascular Surgery, Department of Surgery (J.R., Z.L., Q.W., J.Gi., J.Gr., K.C.K., B.L.) and Department of Ophthalmology and Visual Sciences (N.S.), University of Wisconsin, Madison, Wisconsin; And Department of Vascular Surgery, 2nd Affiliated Hospital School of Medicine, Zhejiang University, Zhejiang, China (Z.L.) liub@surgery.wisc.edu.
Bo
B
Liu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018450:Disease Progression; D004224:Diterpenes / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects; D061251:Primary Cell Culture; D013601:T-Lymphocytes / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004224:Diterpenes; D016023:Integrins; D016328:NF-kappa B; C030419:andrographolide