Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

Abstract

Prostaglandin E(2) (PGE(2)), an important and ubiquitously present vasoactive eicosanoid, may either constrict or dilate systemic vascular beds. However, little is known about the vascular contractile responsiveness to and signaling pathways for PGE(2) at the chronic stage of type 2 diabetes. We hypothesized that PGE(2)-induced arterial contraction is augmented in type 2 diabetic Goto-Kakizaki (GK) rats via the protein kinase Cδ (PKCδ) pathway. Here, we investigated the vasoconstrictor effects of PGE(2) and of sulprostone (EP1-/EP3-receptor agonist) in rings cut from superior mesenteric arteries isolated from GK rats (37-44 weeks old). In arteries from GK rats (vs. those from age-matched Wistar rats), examined in the presence of a nitric oxide synthase inhibitor: 1) the PGE(2)- and sulprostone-induced vasocontractions (which were not blocked by the selective EP1 receptor antagonist sc19220) were enhanced, and these enhancements were suppressed by rottlerin (selective PKCδ inhibitor) but not by Gö6976 (selective PKCα/β inhibitor); 2) the sulprostone-stimulated phosphorylation of PKCδ (at Thr(505)), which yields an active form, was increased and 3) sulprostone-stimulated caldesmon phosphorylations, which are related to isometric force generation in smooth muscle, were increased. The protein expression of EP3 receptor in superior mesenteric arteries was similar between the two groups of rats. Our data suggest that the diabetes-related enhancement of EP3 receptor-mediated vasocontraction results from activation of the PKCδ pathway. Alterations in EP3 receptor-mediated vasocontraction may be important factors in the pathophysiological influences over arterial tone that are present in diabetic states.

Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1

“…Increased formation of vasoconstrictors and altered effectiveness of vasodilators may underlie such impairments. PGE 2 has been demonstrated to function primarily as a vasodilator and vasodepressor when intravenously infused into many species, including humans, dogs, rabbits, mice and rats; however, in certain physiologic settings PGE 2 acts as a vasoconstrictor [12, 16, 17, 38–43]. Our studies indicate that in the presence of Ang II, PGE 2 exhibits vasoconstrictor effects in mouse femoral arteries.…”

Prenatal Testosterone Exposure Induces Hypertension in Adult Females via Androgen Receptor–Dependent Protein Kinase Cδ–Mediated Mechanism

“…In fact, previous studies demonstrated that PKCδ located in smooth muscle directly mediate vasocontractile effects. 54;55;57 Although PKC isoforms have been implicated in contractile responses in dispersed/cultured smooth muscle cells, 58;59 we believe this to be the first instance in which individual PKC isoforms have been specifically identified as being involved in a contractile response in intact vessels, at least when challenged with PDBu. Indeed, the present finding that rottlerin a selective PKCδ inhibitor abrogated hypertension observed in hyperandrogenic rats, indicates a causative role of the heightened PKCδ-mediated signaling in the pathogenesis of androgen-induced hypertension.…”

Effect of Short-term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A₂ Levels in Streptozotocin-Induced Diabetic Mice

“…[8][9][10][11][12][13][14][15][16]27,28) Plasma samples were stored at −20°C until analysis. Briefly, plasma glucose, cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and serum non-esterified fatty acid (NEFA) levels were each determined with a commercially available enzyme kit (Wako Pure Chemical Industries, Ltd., Osaka, Japan).…”

“…The endothelium plays a central role in physiological maintenance of the vascular function by regulating vascular tone, leukocyte adhesion, and platelet activation, as a result of the release of vasoactive substances such as nitric oxide (NO), prostacyclin, and thromboxane A 2 (TXA 2 ). 1,[6][7][8][9][10][11][12][13][14][15][16] Several natural polyphenols have been evaluated for their ability to protect against endothelial dysfunction and, thus, for their effectiveness in preventing cardiovascular disease. 17) Indeed, we have also shown that long-term chlorogenic acid (CA) treatment (2 months) can normalize the impaired endothelium-dependent relaxation seen in diabetic rats.…”