Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality

doi:10.1152/ajpendo.90384.2008

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Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality

Hwee Teoh,¹^,5^,6^,7 Adrian Quan,¹^,6^,7 K. W. Annie Bang,²^,7 Guilin Wang,¹^,6^,7 Fina Lovren,¹^,6^,7 Vivian Vu,¹² Jack J. Haitsma,³^,7 Paul E. Szmitko,⁸ Mohammed Al-Omran,⁹ Chao-Hung Wang,¹⁰ Milan Gupta,¹^,5^,11 Mark D. Peterson,¹^,6^,7 Haibo Zhang,³^,4^,7 Lawrence Chan,¹³ John Freedman,²^,7 Gary Sweeney,¹² and Subodh Verma¹^,5^,6^,7

Divisions of ¹Cardiovascular and Thoracic Surgery, ²Transfusion Medicine, and ³Critical Care, ⁴Department of Anaesthesia, ⁵Cardiometabolic Risk Initiative, ⁶Terrence Donnelly Research Laboratories, ⁷Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital; ⁸Department of General Internal Medicine, University of Toronto, Toronto, Ontario, Canada; ⁹Division of Vascular Surgery, College of Medicine and King Khalid University Hospital, King Saud University-Li Ka Shing Collaborative Research Program, Riyadh, Kingdom of Saudi Arabia; ¹⁰Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; ¹¹Division of Cardiology, William Osler Health Centre, McMaster University, Hamilton; ¹²Department of Biology, York University, Toronto, Ontario, Canada; and ¹³Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas

Submitted 21 April 2008 ; accepted in final form 9 July 2008

Sepsis is a multifactorial, and often fatal, disorder typicallycharacterized by widespread inflammation and immune activationwith resultant endothelial activation. In the present study,we postulated that the adipokine adiponectin serves as a criticalmodulator of survival and endothelial activation in sepsis.To this aim, we evaluated both loss-of-function (adiponectingene-deficient mice) and subsequent gain-of-function (recombinantadiponectin reconstitution) strategies in two well-establishedinflammatory models, cecal ligation perforation (CLP) and thioglyocollate-inducedperitonitis. Adipoq^–/– mice, subjected to CLP, exhibiteda profound ( $~$ 8-fold) reduction in survival compared with theirwild-type Adipoq^+/+ littermates after 48 h. Furthermore, comparedwith wild-type controls, thioglycollate challenge resulted ina markedly greater influx of peritoneal neutrophils in Adipoq^–/–mice accompanied by an excess production of key chemoattractantcytokines (IL-12p70, TNF ${alpha}$ , MCP-1, and IL-6) and upregulationof aortic endothelial adhesion molecule VCAM-1 and ICAM-1 expressions.Importantly, all of these effects were blunted by recombinanttotal adiponectin administration given 3 days prior to thioglycollatechallenge. The protective effects of adiponectin were ascribedlargely to higher-order adiponectin oligomers, since administrationof recombinant C39A trimeric adiponectin did not attenuate endothelialadhesion molecule expression in thioglycollate-challenged Adipoq^–/–mice. These data suggest a critical role of adiponectin as amodulator of survival and endothelial inflammation in experimentalsepsis and a potential mechanistic link between adiposity andincreased sepsis.

adipokine; neutrophil recruitment; cytokines

Address for reprint requests and other correspondence: S. Verma, Div. of Cardiovascular and Thoracic Surgery, Suite 8-003F, Bond Wing, St. Michael's Hospital, 30 Bond St., Toronto, ON, Canada M5B 1W8 (e-mail: subodh.verma{at}sympatico.ca)

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