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Background: The MicroArray Quality Control (MAQC) project evaluated the inter-and intra-

Abstract-Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study. Key Words: fructose Ⅲ insulin resistance Ⅲ hyperinsulinemia Ⅲ hypertension H yperinsulinemia and insulin resistance are closely linked to the development of hypertension in humans and in animal models. [1][2][3] Several mechanisms have been proposed, including the sympathetic nervous system, 4 renal abnormalities in handling sodium, 5,6 and changes in endothelial function and vasoactive mediators such as endothelin-1, nitric oxide, and thromboxane A 2 (TXA 2 ) 3,7,8 However, the exact mechanisms remain to be clarified. Recently, we reported that chronic insulin treatment impaired insulin sensitivity in male and female rats; however, the impairment occurred to a greater degree in male rats. 9 Interestingly, increased blood pressure (BP) was seen only in male rats. These results suggest that the association between hyperinsulinemia/insulin resistance and hypertension is gender-dependent and exists only in male rats. Based on these findings, we speculated that androgens might play an essential role in the relationship between hyperinsulinemia/insulin resistance and hypertension.Gender-associated differences in BP have been widely observed and confirmed in humans. Women during their reproductive years are less prone to hypertension and hypertensionrelated diseases than men or postmenopausal women. 10 Stu...

Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKC␣, -⑀, and -isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKC␦ significantly increased AngII-induced CTGF expression, whereas expression of wild type PKC␦ inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKC␦ (␦Tg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.