Mechanism of thromboxane receptor-induced vasoconstriction in human saphenous vein

Özen, Gülsev; Aljesri, Khadija; Çelik, Zeynep; Türkyilmaz, Gülsüm; Türkyilmaz, Saygın; Teskìn, Önder; Norel, Xavier; Topal, Gökçe

doi:10.1016/j.prostaglandins.2020.106476

Cited by 8 publications

(4 citation statements)

References 72 publications

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“…A further mechanism through which the TP may lead to increased intracellular Ca 2+ is following protein kinase (PK) C activation due to secondmessenger DAG liberation from PIP 2 . It has been shown by multiple groups that TP stimulation in vascular smooth muscle cells leads to dysregulation of resting membrane potential and subsequent activation of LTCCs (75)(76)(77)(78). Mechanistically, Cogolludo et al demonstrated that U46619 treatment of pulmonary artery smooth muscle cells directly inhibits voltagegated K + channels via a PKCζ-mediated mechanism, leading to subsequent depolarization, LTCC-mediated increase in intracellular Ca 2+ , and vasoconstriction (76).…”

Section: Discussionmentioning

confidence: 99%

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

Mulvaney

Renzo

Adão

et al. 2022

Front. Cardiovasc. Med.

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BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction.MethodsThe effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM).ResultsIn the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM.ConclusionThis study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.

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Section: Discussionmentioning

confidence: 99%

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

Mulvaney

Renzo

Adão

et al. 2022

Front. Cardiovasc. Med.

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“…Both α1-adrenoceptor and TP are GPCR expressed on vascular smooth muscle cells and activate G q/11 and G 12/13 signaling pathways. Relaxation responses elicited by vasodilators have been reported to differ between PE versus U46619-contracted tissues, as shown in a recent study on isolated human saphenous veins [ 55 ]. In our study, a decrease in the agonist EDR was not the only evidence of changes to vascular reactivity in the old compared to young SD.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Endothelium-Dependent Relaxation in the Saphenous Artery and Its Caudal Branches in Young and Old Adult Sprague Dawley Rats

2022

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Ageing is associated with reduced endothelium-derived nitric oxide (NO) production in the femoral artery of Sprague Dawley (SD) rats. In the current study, we examined endothelium-dependent relaxation (EDR) in the saphenous artery and its caudal branches. We used acetylcholine and the Proteinase-Activated receptor-2 (PAR2)-specific agonist (2fLIGRLO) with nitroarginine methylester (L-NAME) to assess EDR in two groups of male SD rats (age in weeks: young, 10–12; old, 27–29). Acetylcholine and 2fLIGRLO were potent NO-dependent relaxant agents in all arteries. For all arteries, EDR by acetylcholine decreased significantly in old compared to young SD rats. Interestingly, PAR2-induced EDR of proximal saphenous artery segments and caudal branches decreased significantly in old compared to young, but did not differ for the in-between middle and distal ends of the saphenous artery. L-NAME treatment increased subsequent contractions of proximal and middle segments of saphenous arteries by phenylephrine and U46619 in young, but not in old, SD rats. We conclude the SD saphenous artery and caudal branches exhibit regional characteristics that differ in response to specific EDR agonists, endothelial NO synthase inhibitor, and changes to endothelium function with increased age, which are, in part, attributed to decreased sensitivity of vascular smooth muscle to the gaseous transmitter NO.

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“…COX derived metabolites contribute to the regulation of vascular tone and platelet aggregation. For example, TXA2 is a powerful platelet aggregating factor and vasoconstrictor that is mainly derived from COX-1 while prostacyclin is a potent anti-aggregating agent and vasodilator [ 53 , 54 ]. Homocysteine is known to increase AA metabolites PGD2 and TXB2 by upregulating the expression of the COX enzymes, which might contribute to the endothelial cell activation and platelet aggregation [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

Al‐Shabrawey¹,

Elmarakby²,

Samra³

et al. 2022

Life Res

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Hyperhomocysteinemia (HHcy) contributes to the incidence of many cardiovascular diseases (CVD). Our group have previously established crucial roles of eicosanoids and homocysteine in the incidence of vascular injury in diabetic retinopathy and renal injury. Using cystathionine-β-synthase heterozygous mice (cβs +/− ) as a model of HHcy, the current study was designed to determine the impact of homocysteine on circulating levels of lipid mediators derived from polyunsaturated fatty acids (PUFA). Plasma samples were isolated from wild-type (WT) and cβs +/− mice for the assessment of eicosanoids levels using LC/MS. Plasma 12/15-lipoxygenase (12/15-LOX) activity significantly decreased in cβs +/− vs. WT control mice. LOX-derived metabolites from both omega-3 and omega-6 PUFA were also reduced in cβs +/− mice compared to WT control ( P < 0.05). Contrary to LOX metabolites, cytochrome P450 (CYP) metabolites from omega-3 and omega-6 PUFA were significantly elevated in cβs +/− mice compared to WT control. Epoxyeicosatrienoic acids (EETs) are epoxides derived from arachidonic acid (AA) metabolism by CYP with anti-inflammatory properties and are known to limit vascular injury, however their physiological role is limited by their rapid degradation by soluble epoxide hydrolase (sEH) to their corresponding diols (DiHETrEs). In cβs +/− mice, a significant decrease in the plasma EETs bioavailability was obvious as evident by the decrease in EETs/ DiHETrEs ratio relative to WT control mice. Cyclooxygenase (COX) metabolites were also significantly decreased in cβs +/− vs. WT control mice. These data suggest that HHcy impacts eicosanoids metabolism through decreasing LOX and COX metabolic activities while increasing CYP metabolic activity. The increase in AA metabolism by CYP was also associated with increase in sEH activity and decrease in EETs bioavailability. Dysregulation of eicosanoids metabolism could be a contributing factor to the incidence and progression of HHcy-induced CVD.

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Mechanism of thromboxane receptor-induced vasoconstriction in human saphenous vein

Cited by 8 publications

References 72 publications

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

Characterization of Endothelium-Dependent Relaxation in the Saphenous Artery and Its Caudal Branches in Young and Old Adult Sprague Dawley Rats

Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

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