INTERACTION OF DIABETES AND HYPERTENSION ON DETERMINANTS OF ENDOTHELIAL ADHESIVENESS

Epidemiological studies have established that diabetes mellitus and hy pertension are independent risk factors for atherosclerosis. One of th e earliest abnormalities seen in atherogenesis is enhanced monocyte ad herence to the endothelium. The mechanisms by which diabetes mellitus or hypertension enhances monocyte-endothelial cell interactions are in completely characterized. It is not known whether there are additive i nteractions between these risk factors on endothelial adhesiveness for monocytes. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SH R) rats were fed a normal or fructose-enriched diet. In some cases, an imals were injected with streptozotocin (35 mg/kg body weight) to indu ce diabetes. After 2 weeks, plasma was drawn for biochemical measureme nts, and thoracic aortas were harvested, opened longitudinally, and ex posed to fluorescently labeled mouse monocytoid cells (WEHI 78/24, 2x1 0(6)/mL) for 30 minutes on a rocking platform, Adherent cells were cou nted by epifluorescence microscopy. WEHI 78/24 binding to aortic segme nts from SHR animals was elevated compared with segments from WKYs. Fr uctose feeding alone had no effect on endothelial adhesiveness. When W KYs were made hyperglycemic by STZ injection, monocyte binding was 160 % of the control value. Elevated monocyte binding was also observed in aortas derived from SHR animals injected with STZ, indicating an addi tive effect of hypertension and hyperglycemia. To determine whether al terations in oxidative state played a role in the endothelial adhesive ness, aortic segments were exposed to lucigenin (250 mu mol/L) for mea surement of superoxide anion. Aortic segments from SHR elaborated 120% more superoxide anion than did controls. Elevated free-radical produc tion was also observed in aortas from diabetic WKYs. Furthermore, thor acic aortas derived from diabetic SHR animals elaborated more superoxi de anion than did any of the other groups (374%, P<0.05). Immunohistoc hemical staining for monocyte chemotactic protein-1 demonstrated incre ased expression in aortas isolated from diabetic WKY and SHR compared with control vessels. These studies demonstrate that both diabetes and hypertension lead to increased monocyte adherence to the endothelium. This abnormality is associated with increased vascular superoxide pro duction and monocyte chemotactic protein-1 expression. Furthermore, th ere appears to be an additive interaction between hyperglycemia and hy pertension in their effects on endothelial adhesiveness and its determ inants.