Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Abstract

. Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in noninsulin-dependent diabetic mice induced by high-fat diet and streptozotocin. Am J Physiol Heart Circ Physiol 307: H319 -H327, 2014. First published May 30, 2014 doi:10.1152/ajpheart.00022.2014.-This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1 Ϫ/Ϫ mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1␣, which was abolished in COX-1 Ϫ/Ϫ mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1 Ϫ/Ϫ mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1 Ϫ/Ϫ mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues. diabetes; arachidonic acid; metabolism; thromboxane prostanoid receptors; contraction CYCLOOXYGENASE (COX

Inhibition of cyclooxygenase-2 causes a decrease in coronary flow in diabetic mice. The possible role of PGE2 and dysfunctional vasodilation mediated by prostacyclin receptor

“…Previous studies indicate that the levels of these prostaglandins remain unchanged in the coronary vessels of diabetic rats [13], while increased prostacyclin production has been shown in diabetic mice aorta [9]. It has been also shown that prostacyclin, a prostanoid with a wellestablished role of vasodilator, can become a vasoconstrictor in particular cases [19,4]. This implies that the effects of diabetes on vascular function should always be considered with respect to the particular vascular bed, and any comparisons of the results obtained for different vascular beds should be made with caution.…”

Effect of inflammatory factor‐induced cyclo‐oxygenase expression on the development of reperfusion‐related no‐reflow phenomenon in acute myocardial infarction

“…First, it could inhibit activation of inflammatory cells during no reflow, thereby decreasing endothelial damage . Second, it could decrease the production of endothelium‐derived NO and prostacyclin and thus improve vascular endothelial function . The observations reported herein are the first demonstration that COX has a role in promoting no reflow in rats.…”

Alternatives to the Streptozotocin-Diabetic Rodent

“…Using a low dose of streptozotocin with a high-fat fed C57Bl/6J mouse creates a higher level of blood glucose, which is present in both the fasted and fed state. This type 2 diabetic mouse model has been previously used to examine pharmacological interventions, vascular biology and atherosclerosis, cardiomyocyte hypertrophy, and β-cell function (Bansal et al, 2012; Lin et al, 2015; Lv et al, 2010; Mali et al, 2014; Ullevig, Zhao, Zamora, & Asmis, 2011; Wang, Hsu, Lin, & Chen, 2014; Xue, Ding, & Liu, 2010; Zhu et al, 2014). In our studies comparing the effect of diet-induced obesity, type 1 and type 2 diabetes on neuropathy, we found the severity of hyperglycemia was significantly different between the types 1 and 2 diabetic mouse models (Yorek et al, 2015).…”