This Article Full Text Full Text (PDF) All Versions of this Article: 117/2/216    most recent CIRCULATIONAHA.107.725044v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nishimura, M. Articles by Ouchi, N. Search for Related Content PubMed PubMed Citation Articles by Nishimura, M. Articles by Ouchi, N. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Acute Cerebral Infarction Related Article

(Circulation. 2008;117:216-223.)
© 2008 American Heart Association, Inc.

Stroke

Adiponectin Prevents Cerebral Ischemic Injury Through Endothelial Nitric Oxide Synthase–Dependent Mechanisms

Masaki Nishimura, MD, PhD; Yasuhiro Izumiya, MD, PhD; Akiko Higuchi, MD; Rei Shibata, MD, PhD; Jianhua Qiu, MD, PhD; Chiho Kudo, DDS, PhD; Hwa Kyoung Shin, PhD; Michael A. Moskowitz, MD; Noriyuki Ouchi, MD, PhD

From the Stroke and Neurovascular Regulation Laboratory (M.N., J.Q., C.K., H.K.S., M.A.M.), Department of Neurology and Radiology, Massachusetts General Hospital & Harvard Medical School, Charlestown, Mass, and Molecular Cardiology/Whitaker Cardiovascular Institute (Y.I., A.H., R.S., N.O.), Boston University School of Medicine, Boston, Mass.

Correspondence to Noriyuki Ouchi, MD, PhD, Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St, W611, Boston, MA 02118. E-mail nouchi{at}bu.edu

Received July 6, 2007; accepted November 8, 2007.

Background— Adiponectin is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. A low level of plasma adiponectin is associated with increased mortality after ischemic stroke; however, the causal role of adiponectin in ischemic stroke is unknown.

Methods and Results— To explore the role of adiponectin in the development of acute cerebral injury, we subjected adiponectin-deficient (APN-KO) and wild-type (WT) mice to 1 hour of middle cerebral artery occlusion followed by 23 hours of reperfusion. APN-KO mice exhibited enlarged brain infarction and increased neurological deficits after ischemia-reperfusion compared with WT mice. Conversely, adenovirus-mediated supplementation of adiponectin significantly reduced cerebral infarct size in WT and APN-KO mice. APN-KO mice showed decreased cerebral blood flow during ischemia by laser speckle flowmetry methods. Adiponectin colocalized within the cerebral vascular endothelium under transient ischemic conditions by immunohistochemical analysis. Phosphorylation of endothelial nitric oxide synthase in ischemic brain tissues and the production of nitric oxide metabolites in plasma were attenuated in APN-KO mice compared with WT mice. Adenovirus-mediated administration of adiponectin stimulated endothelial nitric oxide synthase phosphorylation and nitric oxide metabolites during cerebral ischemia in both WT and APN-KO mice. Neuronal nitric oxide synthase expression during ischemia did not differ between WT and APN-KO mice. Adenovirus-mediated delivery of adiponectin did not affect brain infarction in mice deficient in endothelial nitric oxide synthase.

Conclusions— These data provide causal evidence that adiponectin exerts a cerebroprotective action through an endothelial nitric oxide synthase–dependent mechanism. Adiponectin could represent a molecular target for the prevention of ischemic stroke.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 127. [Extract] [Full Text]

This article has been cited by other articles:

				R. Summer, C. A. Fiack, Y. Ikeda, K. Sato, D. Dwyer, N. Ouchi, A. Fine, H. W. Farber, and K. Walsh Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease Am J Physiol Lung Cell Mol Physiol, September 1, 2009; 297(3): L432 - L438. [Abstract] [Full Text] [PDF]

				A. Higuchi, K. Ohashi, S. Kihara, K. Walsh, and N. Ouchi Adiponectin Suppresses Pathological Microvessel Formation in Retina Through Modulation of Tumor Necrosis Factor-{alpha} Expression Circ. Res., May 8, 2009; 104(9): 1058 - 1065. [Abstract] [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances Pharmacol. Rev., March 1, 2009; 61(1): 62 - 97. [Abstract] [Full Text] [PDF]

				M. Kondo, R. Shibata, R. Miura, M. Shimano, K. Kondo, P. Li, T. Ohashi, S. Kihara, N. Maeda, K. Walsh, et al. Caloric Restriction Stimulates Revascularization in Response to Ischemia via Adiponectin-mediated Activation of Endothelial Nitric-oxide Synthase J. Biol. Chem., January 16, 2009; 284(3): 1718 - 1724. [Abstract] [Full Text] [PDF]

				N. Sattar and S. M. Nelson Adiponectin, Diabetes, and Coronary Heart Disease in Older Persons: Unraveling the Paradox J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3299 - 3301. [Full Text] [PDF]