Plasma thromboxane and prostacyclin metabolite ratio in atherosclerosis and diabetes mellitus

Udvardy, M.; Török, I.; Rák, K.

doi:10.1016/0049-3848(87)90463-4

Cited by 17 publications

(3 citation statements)

References 11 publications

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“…While the platelets were originally established as the major source of Tx production (Hamberg et al ., ), the ability of the endothelial cells also to produce Tx was established soon afterwards (Ingerman‐Wojenski et al ., ; Neri Serneri et al ., ). Subsequent studies have identified diverse cellular response to TxA 2 including up‐regulation of adhesion proteins (Ishizuka et al ., ), impaired insulin signalling (Song et al ., ) and atherogenesis and importantly a documented shift towards Tx compared with prostacyclin synthesis in diseases such as diabetes and atherosclerosis (Udvardy et al ., ). Since endothelial TRPV4 channel activation can occur in settings such as atherosclerosis where narrowing of the vessels would increase shear stress or result in turbulent flow, a role for endothelial TRPV4 channel activation as an important source for TxA 2 generation can be postulated.…”

Section: Discussionmentioning

confidence: 97%

GPCR‐mediated EGF receptor transactivation regulates TRPV4 action in the vasculature

Saifeddine

El‐Daly

Mihara

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSETransient receptor potential vanilloid-4 (TRPV4) is a calcium-permeant ion channel that is known to affect vascular function. The ability of TRPV4 to cause a vasoconstriction in blood vessels has not yet been mechanistically examined. Further in neuronal cells, TRPV4 signalling can be potentiated by GPCR activation. Thus, we studied the mechanisms underlying the vascular contractile action of TRPV4 and the GPCR-mediated potentiation of such vasoconstriction, both of which are as yet unappreciated aspects of TRPV4 function. EXPERIMENTAL APPROACHThe mechanisms of TRPV4-dependent regulation of vascular tone in isolated mouse aortae were studied using wire myography. TRPV4-dependent calcium signalling and prostanoid production was studied in cultured human umbilical vein endothelial cells (HUVECs). KEY RESULTSIn addition to the well-documented vasorelaxation response triggered by TRPV4 activation, we report here a TRPV4-triggered vasoconstriction in the mouse aorta that involves a COX-generated Tx receptor (TP) agonist that acts in a MAPK and Src kinase signalling dependent manner. This constriction is potentiated by activation of the GPCRs for angiotensin (AT1 receptors) or proteinases (PAR1 and PAR2) via transactivation of the EGF receptor and a process involving PKC. TRPV4-dependent vascular contraction can be blocked by COX inhibitors or with TP antagonists. Further, TRPV4 activation in HUVECs stimulated Tx release as detected by an ELISA. CONCLUSION AND IMPLICATIONSWe conclude that the GPCR potentiation of TRPV4 action and TRPV4-dependent Tx receptor activation are important regulators of vascular function and could be therapeutically targeted in vascular diseases. IntroductionThe transient receptor potential (TRP) superfamily comprises six families of polymodally activated non-selective cation channels (Clapham, 2003). The vanilloid family member TRPV4 was identified originally as a channel activated by hypotonic cell swelling (Liedtke et al., 2000;Peng and Hediger, 2002). Further studies in knockout mice have established the TRPV4 channel as an osmotic sensor in the CNS (Liedtke and Friedman, 2003). However, subsequent studies have also identified remarkable gating promiscuity with other TRPV4 channel activators including vascular shear stress (Gao et al., 2003;Wu et al., 2007), the phorbol-ester, 4-phorbol 12,13-didecanoate (4α-PDD; Watanabe et al., 2002a), temperature (Guler et al., 2002;Watanabe et al., 2002b), pressure (Suzuki et al., 2003) and low pH (Suzuki et al., 2003). TRPV4 channels are also triggered by anandamide and arachidonic acid subsequent to their P450-epoxygenase-dependent metabolism to the agonist, 5′,6′-epoxyeicosatrienoic acid (Watanabe et al., 2003), which can have antihypertensive activity. Pharmacologically, TRPV4 channels can be activated selectively with the synthetic agonist GSK1016790A (GSK101; Thorneloe et al., 2008;Willette et al., 2008). TRPV4 knockout mice have no overt malformations but have impaired hearing (Tabuchi et al., 2005) and osmoregulation (Li...

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Section: Discussionmentioning

confidence: 97%

GPCR‐mediated EGF receptor transactivation regulates TRPV4 action in the vasculature

Saifeddine

El‐Daly

Mihara

et al. 2015

British J Pharmacology

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“…The pathogenic role of thromboxane A2 (TxA2), a potent platelet aggregating substance and vasoconstrictor generated in platelets, and of its counterpart prostacyclin (PGI2), an antiag gregatory agent and vasodilator mainly synthesized by vascular endothelial cells, in the development and/or progression of atherosclerosis is uncertain. In atherosclerotic patients enhanced levels of thromboxane B2 (TxB2) in plasma (1,2) or in platelet rich plasma following platelet aggregation in vitro (3,4), and an increased urinary excretion of thromboxane metabolites were reported by several investigators (5). PGI2 production of isolated vascular tissue obtained from patients with severe atherosclerosis has been found to be either reduced (6,7) or unchanged (8) compared with the controls.…”

Section: Introductionmentioning

confidence: 98%

Thromboxane A2 and Prostacyclin Generation in the Microvasculature of Patients with Atherosclerosis – Effect of Low-Dose Aspirin

et al. 1989

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SummaryGeneration of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1α, 6-keto- PGF1α) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a >90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PcF1α levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples.We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

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“…At the same time, diabetes is associated with a decreased production of vasodilating and antiaggregatory prostacyclin by endothelium in certain vascular beds . These two phenomena contribute to an imbalance between anti‐ and proaggregatory prostanoids in favour of the latter . Another consequence of an increased platelet reactivity is their enhanced potential for adhering to the wall of blood vessels, which in turn sets conditions for development of atherosclerosis .…”

Section: Introductionmentioning

confidence: 99%

Effects of three‐month streptozotocin‐induced diabetes in mice on blood platelet reactivity, COX‐1 expression and adhesion potential

Przygodzki

Kassassir

Talar

et al. 2019

Int J Experimental Path

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Diabetes is associated with an increased risk of cardiovascular disease. This is partially attributed to an altered activation status of blood platelets in this disease. Previously, alterations have been shown in COX-1 and protease activated receptor (PAR)-3 receptor expression in platelets in two animal models of diabetes, there have not been studies which address expression of these proteins in mice with long-term streptozotocin (STZ)-induced diabetes. We have also addressed the effect of diabetes on platelet adhesion under flow conditions. With the use of flow cytometry, we have shown that certain markers of platelet basal activation, such as active form of α IIb β 3 and of CD40L were increased in STZ-induced diabetic mice. Platelets from STZ-induced diabetic mice were also more reactive when stimulated with PAR-4 activating peptide as revealed by higher expression of active form of α IIb β 3 , membrane-bound on vWillebrand Factor and binding of exogenous fluorescein isothyanate-labelled fibrinogen.Expression of COX-1 and production of thromboxane A 2 in platelets of STZ-induced diabetic mice were higher than in control animals. We observed no effect of diabetes on ability of platelets to form stable adhesions with fibrinogen in flow conditions. We conclude that although certain similarities exist between patterns of activation of platelets in animal models of diabetes, the differences should also be taken into account. K E Y W O R D Scell adhesion, diabetes, platelets, prostanoids 42 | PRZYGODZKI et al.

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Plasma thromboxane and prostacyclin metabolite ratio in atherosclerosis and diabetes mellitus

Cited by 17 publications

References 11 publications

GPCR‐mediated EGF receptor transactivation regulates TRPV4 action in the vasculature

GPCR‐mediated EGF receptor transactivation regulates TRPV4 action in the vasculature

Thromboxane A2 and Prostacyclin Generation in the Microvasculature of Patients with Atherosclerosis – Effect of Low-Dose Aspirin

Effects of three‐month streptozotocin‐induced diabetes in mice on blood platelet reactivity, COX‐1 expression and adhesion potential

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