The central purpose of this application is to characterize porcine models by endocrine, metabolic, and cardiovascular criteria to determine if they are suitable models of coronary artery disease (CAD) in human diabetes. This project does not fall in the categorical interest of only a single NIH Institute, because these are integrated studies of diabetes (NIDDK) and vascular biology (NHLBI). The experimental design is to study pigs having high fat diet-induced dyslipidemia combined with alloxan-induced diabetes. The porcine model enables tight control of these variables, invasive measures of CAD, and provides ample plasma and arteries for in vitro tissue and cell studies. The ability to monitor swine serially over many weeks of treatment facilitates study of CAD development in diabetes, which has not been possible in widely used rodent and transgenic mouse models.
The Specific Aims are: 1) Describe the endocrine and metabolic indices of diabetes. An insulin sensitivity test that is more practical for swine will be developed to determine which types of diabetes these porcine models best represent; 2) Describe diabetic dyslipidemia. Traditional and """"""""nontraditional"""""""" lipids, including oxidized low density lipoprotein (LDL), glycated LDL, and nutritional antioxidants will describe unique features of a diabetic """"""""risk factor profile;"""""""" 3) Determine the time course of progression of the diabetic """"""""risk factor profile"""""""" relative to in vitro intravascular ultrasound (IVUS) measures of functional CAD and structural CAD. Invasive IVUS measures of conduit artery atheroma, diameter, and Doppler flow measures of coronary flow will distinguish between microvascular and microvascular CAD; 4) Describe the extent of coronary artery functional CAD and structural CAD in vitro. Fatty streak measures and in vitro contraction and endothelium-dependent relaxation of coronary rings to vasoactive agents will provide other endpoints of CAD; 5) Correlate smooth muscle and endothelial calcium with CAD. The applicants will determine whether single cell calcium alterations parallel in vivo and in vitro coronary vasoreactivity; and 6) Describe the extent of restenosis after coronary atherectomy. Since diabetics have a 2-fold higher incidence of restenosis after balloon angioplasty, the applicants will determine whether the prognosis is better with atherectomy. The development of porcine models provides the fundamental basis for virtually all of the applicant's future studies, including pharmacotherapy, exercise training, and detailed studies of cellular/molecular mechanisms of CAD in diabetes.
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