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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/H845    most recent 00134.2005v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Sista, A. K. Articles by Tsao, P. S. Search for Related Content PubMed PubMed Citation Articles by Sista, A. K. Articles by Tsao, P. S.

Increased aortic stiffness in the insulin-resistant Zucker fa/fa rat

¹Division of Cardiovascular Sciences, School of Medicine, and ²Department of Mechanical Engineering, Stanford University, Stanford, California

Submitted 10 February 2005 ; accepted in final form 24 March 2005

Accumulating clinical evidence indicates increased aortic stiffness, an independent risk factor for cardiovascular and all-cause mortality, in type 2 diabetic and glucose-intolerant individuals. The present study sought to determine whether increased mechanical stiffness, an altered extracellular matrix, and a profibrotic gene expression profile could be observed in the aorta of the insulin-resistant Zucker fa/fa rat. Mechanical testing of Zucker fa/fa aortas showed increased vascular stiffness in longitudinal and circumferential directions compared with Zucker lean controls. Unequal elevations in developed strain favoring the longitudinal direction resulted in a loss of anisotropy. Real-time quantitative PCR and immunohistochemistry revealed increased expression of fibronectin and collagen IV₃ in the Zucker fa/fa aorta. In addition, expression of transforming growth factor- and several Smad proteins was increased in vessels from insulin-resistant animals. In rat vascular smooth muscle cells, 12–18 h of exposure to insulin (100 nmol/l) enhanced transforming growth factor-1 mRNA expression, implicating a role for hyperinsulinemia in vascular stiffness. Thus there is mechanical, structural, and molecular evidence of arteriosclerosis in the Zucker fa/fa rat at the glucose-intolerant, hyperinsulinemic stage.

extracellular matrix; type 2 diabetes; arterial compliance; insulin resistance; transforming growth factor-

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