Abstract 503: PKCβ Modulates Accelerated Initiation and Progression of Atherosclerosis in Diabetic Mice
Accelerated initiation and progression of atherosclerosis is the most common macrovascular complication of diabetes. Increasing evidence links hyperglycemia to diabetic microvascular complications via activation of protein kinase C (PKC) β, a molecule involved in signal transduction in response to vascular injury. We previously reported that mice lacking both apolipoprotein E (apoE) and PKCβ displayed significantly decreased atherosclerosis in euglycemia. Here, we tested the hypothesis that genetic deletion of PKCβ would attenuate the accelerated initiation and progression of diabetic atherosclerosis. ApoE and PKCβ/apoE null mice were rendered diabetic by injection of streptozotocin (65μg/g weight) for five consecutive days at age 6 weeks. The mice were sacrificed after 6 weeks of confirmed diabetes or control state. Plasma glucose was 409.8 ± 34.1 mg/dl in diabetic apoE null vs 374.7 ± 89.3 mg/dl in diabetic PKCβ/apoE (p=0.69). At age 14 weeks, mean atherosclerotic lesion area at the aortic root was significantly decreased in diabetic PKCβ/apoE (26,732.8 ± 9,430 μm2) compared to that in diabetic apoE null mice (93,864.7 ± 8,056 μm2) (N≥7/group, p<0.0001), and citrate-treated non-diabetic apoE null mice (65,612.1 ± 13,875 μm2) (N≥6, p<0.005), respectively. Consistent with a role for PKCβ in lesion progression, the lesion complexity index was also significantly decreased in the diabetic PKCβ/apoE (0.167 ± 0.167) versus diabetic apoE null mice (1.0 ± 0.0) (p=0.0019). There were no significant differences in levels of plasma triglyceride between the two groups (72.46 ± 9.7 vs. 99.97 ± 3.6 mg/dl, p=0.6), nor of total cholesterol (442.9 ± 97.8 vs. 432.9 ± 82.6 mg/dl, p=0.83). Western Blot analysis of aorta for early growth resonse-1 (Egr-1) antigen, a key downstream target involved in atherogenesis which triggers pleiotropic inflammatory and thrombotic cascades, was decreased 2.3-fold in diabetic PKCβ/apoE mice vs. diabetic apoE null mice (p<0.0001). These data critically link PKCβ to accelerated initiation and progression of diabetic atherosclerosis. We conclude that these studies may expand the repertoire of potential therapeutic application of PKCβ antagonism (ruboxistaurin) to diabetic macrovascular disease.