Arachidonic Acid Metabolite 19(S)-HETE Induces Vasorelaxation and Platelet Inhibition by Activating Prostacyclin (IP) Receptor

19(S)-hydroxy-eicosatetraenoic acid (19(S)-HETE) belongs to a family of arachidonic acid metabolites produced by cytochrome P450 enzymes, which play critical roles in the regulation of cardiovascular, renal and pulmonary functions. Although it has been known for a long time that 19(S)-HETE has vascular effects, its mechanism of action has remained unclear. In this study we show that 19(S)-HETE induces cAMP accumulation in the human megakaryoblastic leukemia cell line MEG-01. This effect was concentration-dependent with an EC50 of 520 nM, insensitive to pharmacological inhibition of COX-1/2 and required the expression of the G-protein G(s). Systematic siRNA-mediated knock-down of each G-protein coupled receptor (GPCR) expressed in MEG-01 followed by functional analysis identified the prostacyclin receptor (IP) as the mediator of the effects of 19(S)-HETE, and the heterologously expressed IP receptor was also activated by 19(S)-HETE in a concentration- dependent manner with an EC50 of 567 nM. Pretreatment of isolated murine platelets with 19(S)-HETE blocked thrombin-induced platelets aggregation, an effect not seen in platelets from mice lacking the IP receptor. Furthermore, 19(S)-HETE was able to relax mouse mesenteric artery-and thoracic aorta-derived vessel segments. While pharmacological inhibition of COX-1/2 enzymes had no effect on the vasodilatory activity of 19(S)HETE these effects were not observed in vessels from mice lacking the IP receptor. These results identify a novel mechanism of action for the CYP450-dependent arachidonic acid metabolite 19(S)-HETE and point to the existence of a broader spectrum of naturally occurring prostanoid receptor agonists

Development of a new method to determine dynamic tensile strength of ballistic yarns

Since the design of new soft protections is getting intensive, the study of the dynamic behavior of ballistic yarns becomes more and more important. This paper deals with the development of a new experimental method in order to obtain some dynamic parameters by performing dynamic tensile tests. The concept is quite simple: two projectiles, linked together by the ballistic yarn we want to study, are accelerated together with the help of a gas gun. The first one flies freely while the second one is suddenly stopped. The yarn is then loaded in tensile. Several measurements are performed during each test with the help of a high speed camera. First results on a polyethylene yarn are presented here and several improvements are proposed in order to improve the accuracy of the results

LPA(1) receptor-mediated thromboxane A(2) release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction

Lysophosphatidic acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA(1), LPA(2), LPA(4), and LPA(6). In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA(1–3) agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA(1&3) antagonist Ki16425, and genetic deletion of LPA(1) but not that of LPA(2) or inhibition of LPA(3), by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A(2) (TXA(2)) release from TA of wild-type, TP-KO, and LPA(2)-KO mice but not from LPA(1)-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA(1)-, G(i)-, and COX1-dependent autocrine/paracrine TXA(2) release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA(1) and TXA(2)/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.—Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklós, Z., Nüsing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyó, Z. LPA(1) receptor-mediated thromboxane A(2) release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction

Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis

The activation and differentiation of cancer-associated fibro-blasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE(2)) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE(2) signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGF beta-activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression. Significance: The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis. [GRAPHICS