Increased aortic stiffness in the insulin-resistant Zucker fa/fa rat.
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-beta1 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.
Sista
Akhilesh K
AK
Division of Cardiovascular Sciences, Dept. of Cardiovascular Medicine, Stanford School of Medicine, 300 Pasteur Dr., Stanford, CA 94305, USA.
O'Connell
Mary K
MK
Hinohara
Tomoya
T
Oommen
Santosh S
SS
Fenster
Brett E
BE
Glassford
Alexander J
AJ
Schwartz
Eric A
EA
Taylor
Charles A
CA
Reaven
Gerald M
GM
Tsao
Philip S
PS
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D004548:Elasticity; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D016326:Extracellular Matrix Proteins; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1