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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 58; 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: Bethesda, MD American Physiological Society 01.08.2005
• Subjects: Biological and medical sciences; Coronary vessels; Diabetes; Fundamental and applied biological sciences. Psychology; Gene expression; Insulin; Proteins; Rodents; Vertebrates: cardiovascular system; Endocrinopathy; Type 2 diabetes; Pancreatic hormone; Rat; arterial compliance; Transforming growth factor β; Rodentia; Metabolic diseases; Insulin; Vertebrata; Mammalia; transforming growth factor-β; Insulin resistance; Extracellular matrix; Stiffness; Circulatory system
• ISSN: 0363-6135; 1522-1539

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{alpha}3 in the Zucker fa/fa aorta. In addition, expression of transforming growth factor-{beta} 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-{beta}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. [PUBLICATION ABSTRACT]