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Molecular and Cellular Biology, July 2009, p. 3487-3499, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.00126-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism ^,

Koji Ohashi,¹ Noriyuki Ouchi,^1* Kaori Sato,¹ Akiko Higuchi,¹ Tomo-o Ishikawa,² Harvey R. Herschman,² Shinji Kihara,³ and Kenneth Walsh^1*

Molecular Cardiology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118,¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095,² Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan³

Received 27 January 2009/ Returned for modification 24 March 2009/ Accepted 16 April 2009

Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induced revascularization was impaired in mice in which the Cox-2 gene is deleted in Tie2-Cre-expressing cells. Adenovirus-mediated overexpression of adiponectin enhanced COX-2 expression and revascularization of ischemic limbs in control mice, but not in targeted Cox-2-deficient mice. In cultured endothelial cells, adiponectin protein increased COX-2 expression, and ablation of COX-2 abrogated the adiponectin-stimulated increases in endothelial cell migration, differentiation, and survival. Ablation of calreticulin (CRT) or its adaptor protein CD91 diminished adiponectin-stimulated COX-2 expression and endothelial cell responses. These observations provide evidence that adiponectin promotes endothelial cell function through CRT/CD91-mediated increases in COX-2 signaling. Thus, disruption of the adiponectin-COX-2 regulatory axis in endothelial cells could participate in the pathogenesis of obesity-related vascular diseases.

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* Corresponding author. Mailing address: Molecular Cardiology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118. Phone: (617) 414-2392. Fax: (617) 414-2391. E-mail for Kenneth Walsh: kxwalsh{at}bu.edu. E-mail for Noriyuki Ouchi: nouchi{at}bu.edu

Published ahead of print on 27 April 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, July 2009, p. 3487-3499, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.00126-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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