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UBC Theses and Dissertations

Mechanisms of vascular dysfunction in diabetes and hypertension Nagareddy, Prabhakara Reddy

Abstract

Cardiovascular complications of diabetes are related in part to abnormal vascular function, a manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. We investigated the biochemical and functional consequences of diabetes and metabolic abnormalities, particularly insulin resistance, on vascular function, using two different animal models, the streptozotocin (STZ)-diabetic rat model of type 1 diabetes and the high fructose diet-fed rat model of insulin resistance and hypertension (FHR). In STZ diabetic rats, we found that complex biochemical interactions led to changes in hemodynamic variables. Specifically, we found that increased activation of PKCβ2 leads to induction of inducible nitric oxide synthase (iNOS), which results in increased production of both nitric oxide and peroxynitrite, causing pressor hypo-responsiveness, depressed cardiac function, mean arterial blood pressure and heart rate and impaired endothelial function in STZ-diabetic rats. Further, we found that hyperglycemia-induced activation of PKCβ2 is antecedent to increases in oxidative stress, activation of ERK1/2, NF-κB, and iNOS expression, and the protective effects of PKCβ or iNOS inhibition in STZ diabetic rats are associated with inhibition of iNOS-mediated peroxynitrite formation. In contrast to STZ diabetic rats, endothelial dysfunction in FHR is associated with hypertension. In FHR, we investigated the role of matrix metalloproteinases (MMP) and epidermal growth factor receptor (EGFR) transactivation, a novel pathway that has been proposed to link all the pathological features of hypertension including endothelial dysfunction, enhanced vascular tone and hypertrophic growth of cardiovascular tissue. We found that in normal arteries, MMP-EGFR pathway modulates vascular tone, at least in part, via activation of PI3-kinase and mitochondrial ATP synthesis. In FHR arteries, inhibition of MMPs by doxycycline improved endothelial function while EGFR inhibition by AG1478 promoted vasorelaxation. Further, in insulin resistant vascular smooth muscle cells and arteries from FHR, pharmacological or siRNA inhibition of MMP-EGFR signaling normalized the increased expression and activity of contractile proteins (MLCK, MLC II) and their transcriptional activators (P90RSK and SRF) in addition to the prevention of hypertension in FHR. Our data suggests that the MMP-EGFR pathway could be a potential target in the treatment of hypertension.

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