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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 289; no. 2; pp. H845 - H851
• Main Authors: Sista, Akhilesh K, O'Connell, Mary K, Hinohara, Tomoya, Oommen, Santosh S, Fenster, Brett E, Glassford, Alexander J, Schwartz, Eric A, Taylor, Charles A, Reaven, Gerald M, Tsao, Philip S
• Format: Journal Article
• Language: English
• Published: United States 01.08.2005
• Subjects: Animals; Aorta - metabolism; Aorta - physiopathology; Elasticity; Extracellular Matrix Proteins - metabolism; Insulin Resistance; Male; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; Obesity - metabolism; Obesity - physiopathology; Rats; Rats, Zucker; Signal Transduction; Tissue Culture Techniques; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1; Up-Regulation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00134.2005

1 Division of Cardiovascular Sciences, School of Medicine, and 2 Department 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 IV 3 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- Address for reprint requests and other correspondence: P. Tsao, Dept. of Cardiovascular Medicine, Stanford School of Medicine, 300 Pasteur Dr., Stanford, CA 94305 (E-mail: ptsao{at}stanford.edu )