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1.
Bioengineered ; 13(4): 10038-10046, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35416124

RESUMO

Praeruptorin A (PA) is a natural coumarin compound from the roots of Radix Peucedani and is commonly used in the treatment of certain respiratory diseases and hypertension. Although previous studies identified relaxant effects of PA on tracheal and arterial preparations, little is known about its vasodilative effects and underlying mechanisms. Here, an organ bath system and tension recording methods were used to prepare and analyze isolated rat thoracic aorta artery rings. Aorta artery rings were pre-contracted with phenylephrine and then incubated with PA, and the possible mechanism of relaxation was investigated by adding inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), endothelial nitric oxide synthase (L-NG-nitroarginine, L-NNA), cyclooxygenase (indomethacin), guanylyl cyclase (1 H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one, ODQ), and KCa channels (tetraethylammonium, TEA). Our study showed that PA-induced vasodilation was blocked by L-NAME, L-NNA, and ODQ, while CaCl2-induced vasoconstriction was countered by PA. Thus, PA may exert a vasodilatory effect by influencing the amounts of endothelium-derived relaxing factors through endothelial-dependent NO-cGMP and prostacyclin pathways (such as NO and prostacyclin 2). In the rat thoracic aorta, PA reduces vasoconstriction by inhibiting Ca2+ inflow.


Assuntos
Aorta Torácica , Vasodilatadores , Animais , Aorta Torácica/metabolismo , Cumarínicos , Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacologia , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Vasodilatadores/metabolismo , Vasodilatadores/farmacologia
2.
Biomed Pharmacother ; 148: 112786, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35259564

RESUMO

BACKGROUND: Non-allergic angioedema is a potentially life-threatening condition caused by accumulation of bradykinin and subsequent activation of bradykinin type 2 receptors (B2). Since COX activity plays a pivotal role in B2 signaling, the aim of this study was to determine which prostaglandins are the key mediators and which COX, COX-1 or COX-2, is predominantly involved. METHODS: We used Miles assays to assess the effects of inhibitors of COX, 5-lipoxygenase, epoxyeicosatrienoic acid generation, cytosolic phospholipase A2α and a variety of prostaglandin receptor antagonists on bradykinin-induced dermal extravasation in C57BL/6 and COX-1-deficient mice (COX-1-/-). In addition, the prostacyclin metabolite 6-keto-PGF1α was quantified by ELISA in subcutaneous tissue from C57BL/6 and human dermal microvascular endothelial cells. In the latter, 6-keto-PGF1α was also quantified and identified by LC-MS/MS. RESULTS: Unspecific COX inhibition by ibuprofen and diclofenac significantly reduced B2-mediated dermal extravasation in C57BL/6 but not COX-1-/-. Likewise, inhibition of cytosolic phospholipase A2α showed similar effects. Furthermore, extravasation in COX-1-/- was generally lower than in C57BL/6. Of the prostaglandin antagonists used, only the prostacyclin receptor antagonist RO1138452 showed a significant reduction of dermal extravasation. Moreover, 6-keto-PGF1α concentrations were increased after bradykinin treatment in subcutaneous tissue from C57BL/6 as well as in human dermal microvascular endothelial cells and this increase was abolished by diclofenac. CONCLUSION: Our findings suggest that COX-1-dependent prostacyclin production is critically involved in dermal extravasation after activation of B2 in small dermal blood vessels. Targeting prostacyclin production and/or signaling appears to be a suitable option for acute treatment of non-allergic angioedema.


Assuntos
Angioedema/patologia , Ciclo-Oxigenase 1/metabolismo , Epoprostenol/metabolismo , Angioedema/induzido quimicamente , Animais , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Araquidônico/metabolismo , Bradicinina/farmacologia , Diclofenaco/farmacologia , Células Endoteliais/efeitos dos fármacos , Fosfolipases A2 do Grupo IV/efeitos dos fármacos , Fosfolipases A2 do Grupo IV/metabolismo , Ibuprofeno/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigenases/efeitos dos fármacos , Oxigenases/metabolismo , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores
3.
Int J Mol Sci ; 23(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35162966

RESUMO

The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality.


Assuntos
Doenças Cardiovasculares/complicações , Epoprostenol/metabolismo , Óxido Nítrico/metabolismo , Tromboembolia/metabolismo , Adenilil Ciclases/metabolismo , Doenças Cardiovasculares/metabolismo , Resistência a Medicamentos , Humanos , Estresse Oxidativo , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo , Tromboembolia/etiologia
4.
Eur J Pharmacol ; 923: 174700, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35131313

RESUMO

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a fatal disease caused by the progressive remodeling of pulmonary arteries (PAs). Treprostinil (TPS) is a tricyclic benzidine prostacyclin clinically used for PAH treatment. However, due to low bioavailability, short half-times, and severe systemic side effects, TPS efficacy remains limited. METHODS: In this study, glucuronic acid (GlcA)-modified liposomes were developed to improve the site-specific delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) by targeting the glucose transporter-1 (GLUT-1) in vitro and in vivo. RESULTS: Non-GlcA-modified and GlcA-modified liposomes encapsulating TPS were 106 ± 1.12 nm in diameter. The drug encapsulation efficiency (EE) was 92%. Data from rat PASMCs showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration by suppressing growth factor expression, including transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and cAMP, which was possibly mediated by the cAMP-C/EBP-α p42-p21 signaling pathway. In PAH model rats, GlcA-modified liposomes significantly improved TPS bioavailability and sustained its release over time. Most importantly, the selective inhibition of pulmonary arterial pressure, rather than systemic arterial pressure, indicated the increased pulmonary-specific accumulation of TPS. Of the three TPS formulations, TPS-loaded GlcA-modified liposomes exhibited the most potent activity by inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition in PAs, and attenuating right ventricle hypertrophy (RVH) in sugen-5416-induced PAH rats. CONCLUSIONS: The GLUT-1-targeted delivery of TPS increased pulmonary specificity and enhanced TPS anti-PAH activities in vivo and in vitro.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Proliferação de Células , Epoprostenol/análogos & derivados , Epoprostenol/metabolismo , Hipertensão Pulmonar Primária Familiar , Lipossomos/metabolismo , Lipossomos/farmacologia , Lipossomos/uso terapêutico , Miócitos de Músculo Liso , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar , Ratos , Remodelação Vascular
5.
FASEB J ; 35(10): e21952, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34555210

RESUMO

Cyclophosphamide (CP) has been widely used in the treatment of various malignancies and autoimmune diseases, but acrolein, a byproduct of CP, causes severe hemorrhagic cystitis as the major side effect of CP. On the other hand, a large amount of prostacyclin (PGI2 ) is produced in bladder tissues, and PGI2 has been shown to play a critical role in bladder homeostasis. PGI2 is biosynthesized from prostaglandin (PG) H2 , the common precursor of PGs, by PGI2 synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI2 in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI2 -IP (PGI2 receptor) signaling exacerbated CP-induced bladder inflammatory reactions. Ptgis deficiency attenuated CP-induced vascular permeability and chemokine-mediated neutrophil migration into bladder tissues and then suppressed hemorrhagic cystitis. Treatment with RO1138452, an IP selective antagonist, also suppressed CP-induced cystitis. We further found that cystitis-related nociceptive behavior was also relieved in both Ptgis-/- mice and RO1138452-treated mice. Our findings may provide new drug targets for bladder inflammation and inflammatory pain in CP-induced hemorrhagic cystitis.


Assuntos
Ciclofosfamida/efeitos adversos , Cistite/induzido quimicamente , Cistite/prevenção & controle , Epoprostenol/deficiência , Dor/prevenção & controle , Bexiga Urinária , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Quimiotaxia de Leucócito , Cistite/complicações , Sistema Enzimático do Citocromo P-450/deficiência , Progressão da Doença , Epoprostenol/metabolismo , Feminino , Hemorragia/complicações , Hemorragia/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Tamanho do Órgão/efeitos dos fármacos , Dor/induzido quimicamente , Dor/complicações , Prostaglandina-E Sintases , Bexiga Urinária/efeitos dos fármacos
6.
Mediators Inflamm ; 2021: 9951946, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34475805

RESUMO

OBJECTIVES: Dendrobium catenatum Lindl. (DH) is a Chinese herbal medicine, which is often used to make tea to improve immunity in China. Rumor has it that DH has a protective effect against cardiovascular disease. However, it is not clear how DH can prevent cardiovascular disease, such as atherosclerosis (AS). Therefore, the purpose of this study is to study whether DH can prevent AS and the underlying mechanisms. METHODS: Zebrafish larvae were fed with high-cholesterol diet (HCD) to establish a zebrafish AS model. Then, we used DH water extracts (DHWE) to pretreat AS zebrafish. The plaque formation was detected by HE, EVG, and oil red O staining. Neutrophil and macrophage counts were calculated to evaluate the inflammation level. Reactive oxygen species (ROS) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity in zebrafish were measured to reflect oxidative stress. The cholesterol accumulation and the levels of lipid, triglyceride (TG), and total cholesterol (TC) were measured to reflect lipid metabolism disorder. Then, parallel flow chamber was utilized to establish a low shear stress- (LSS-) induced endothelial cell (EC) dysfunction model. EA.hy926 cells were exposed to LSS (3 dyn/cm2) for 30 min and treated with DHWE. The levels of ROS, SOD, MDA, glutathione (GSH), and glutathiol (GSSG) in EA.hy926 cells were analysed to determine oxidative stress. The release of nitric oxide (NO), endothelin-1 (ET-1), and epoprostenol (PGI2) in EA.hy926 cells was measured to reflect EC dysfunction. The mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in EA.hy926 cells was detected to reflect EC dysfunction inflammation. RESULTS: The results showed that DHWE significantly reduced cholesterol accumulation and macrophage infiltration in early AS. Finally, DHWE significantly alleviate the lipid metabolism disorder, oxidative stress, and inflammation to reduce the plaque formation of AS zebrafish larval model. Meanwhile, we also found that DHWE significantly improved LSS-induced EC dysfunction and oxidative stress in vitro. CONCLUSION: Our results indicate that DHWE could be used as a prevention method to prevent AS.


Assuntos
Aterosclerose/tratamento farmacológico , Dendrobium/metabolismo , Coração/embriologia , Água/química , Peixe-Zebra/embriologia , Animais , Linhagem Celular , Colesterol na Dieta , Medicamentos de Ervas Chinesas , Endotelina-1/biossíntese , Epoprostenol/metabolismo , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/biossíntese , Óxido Nítrico/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio , Resistência ao Cisalhamento , Estresse Mecânico , Triglicerídeos/sangue , Veias Umbilicais/metabolismo
7.
FASEB J ; 35(9): e21877, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34449098

RESUMO

Although commonly thought to produce prostacyclin (prostaglandin I2 ; PGI2 ) that evokes vasodilatation and protects vessels from the development of diseases, the endothelial cyclooxygenase (COX)-mediated metabolism has also been found to release substance(s) called endothelium-derived contracting factor(s) (EDCF) that causes endothelium-dependent contraction and implicates in endothelial dysfunction of disease conditions. Various mechanisms have been proposed for the process; however, the major endothelial COX metabolite PGI2 , which has been classically considered to activate the I prostanoid receptor (IP) that mediates vasodilatation and opposes the effects of thromboxane (Tx) A2 produced by COX in platelets, emerges as a major EDCF in health and disease conditions. Our recent studies from genetically altered mice further suggest that vasomotor reactions to PGI2 are collectively modulated by IP, the vasoconstrictor Tx-prostanoid receptor (TP; the prototype receptor of TxA2 ) and E prostanoid receptor-3 (EP3; a vasoconstrictor receptor of PGE2 ) although with differences in potency and efficacy; a contraction to PGI2 reflects activities of TP and/or EP3 outweighing that of the concurrently activated IP. Here, we discuss the history of endothelium-dependent contraction, evidences that support the above hypothesis, proposed mechanisms for the varied reactions to endothelial PGI2 synthesis as well as the relation of its dilator activity to the effect of another NO-independent vasodilator mechanism, the endothelium-derived hyperpolarizing factor. Also, we address the possible pathological and therapeutic implications as well as questions remaining to be resolved or limitations of our above findings obtained from genetically altered mouse models.


Assuntos
Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Vasoconstrição/fisiologia , Animais , Endotélio Vascular/efeitos dos fármacos , Humanos , Camundongos , Prostaglandinas/metabolismo , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos/metabolismo , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/metabolismo
8.
Mol Biol Rep ; 48(7): 5503-5511, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34291395

RESUMO

BACKGROUND: Although high doses of proton pump inhibitors can elicit an anticancer effect, this strategy may impair vascular biology. In particular, their effects on endothelial Ca2+ signaling and production of endothelium-derived relaxing factor (EDRF) are unknown. To this end, we investigated the effects of high dosages of omeprazole on endothelial Ca2+ responses and EDRF production in primary cultured porcine aortic endothelial cells. METHODS AND RESULTS: Omeprazole (10-1000 µM) suppressed both bradykinin (BK)- and thapsigargin-induced endothelial Ca2+ response in a dose-dependent manner. Furthermore, omeprazole slightly attenuated Ca2+ mobilization from the endoplasmic reticulum, whereas no inhibitory effects on endoplasmic reticulum Ca2+-ATPase were observed. Omeprazole decreased BK-induced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and tended to decrease BK-induced nitric oxide production. Production of prostaglandin I2 metabolites, especially 6-keto-prostaglandin 1α, also tended to be reduced by omeprazole. CONCLUSION: Our results are the first to indicate that high doses of omeprazole may suppress both store-operated Ca2+ channels and partially the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, and decreased BK-induced, Ca2+-dependent phosphorylation of eNOS(Ser1177). Thus, high dosages of omeprazole impaired EDRF production by attenuating intracellular Ca2+ signaling.


Assuntos
Aorta/citologia , Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Omeprazol/farmacologia , Animais , Bradicinina/metabolismo , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Óxido Nítrico/metabolismo , Fosforilação , Suínos
9.
DNA Cell Biol ; 40(10): 1231-1234, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34265210

RESUMO

Tregulatory cells (Tregs) are an important member of the adaptive immune system and function to reduce and resolve inflammation. Prostaglandin I2 (PGI2) is a lipid mediator that has potent anti-inflammatory effects on immune cells. Several studies have investigated the interplay between PGI2 and Tregs. Together, the data from these studies demonstrate that PGI2 promotes the formation and function of Tregs. This suggests that therapeutic supplementation of PGI2 may be a treatment for various autoimmune or inflammatory diseases through enhancement of Treg function.


Assuntos
Epoprostenol/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anti-Inflamatórios/farmacologia , Doenças Autoimunes/tratamento farmacológico , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Humanos , Linfopoese , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos
10.
J Cardiovasc Pharmacol Ther ; 26(5): 453-462, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836637

RESUMO

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I2) (PGI2) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI2 pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI2 signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.


Assuntos
Anti-Hipertensivos/farmacologia , Epoprostenol/farmacologia , Óxido Nítrico/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Quimioterapia Combinada , Epoprostenol/metabolismo , Humanos , Óxido Nítrico/metabolismo , Fenilpropionatos , Hipertensão Arterial Pulmonar/fisiopatologia , Piridazinas , Tadalafila
11.
Drug Discov Today ; 26(6): 1420-1436, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33677145

RESUMO

The placenta has vital roles in metabolite exchange, fetal growth, and pre-eclampsia (PE). In this review, we discuss the pathogenesis of hypertension in pregnancy, focusing on four major theories to explain PE, discussing endothelial roles in those theories. We focus in particular on the roles of nitric oxide (NO) and prostacyclin (PGI2) in placental endothelium, and propose new hypotheses for the influence and mechanisms of endothelial NO and PGI2 signaling pathways in PE.


Assuntos
Endotélio Vascular/patologia , Placenta/irrigação sanguínea , Pré-Eclâmpsia/fisiopatologia , Animais , Epoprostenol/metabolismo , Feminino , Humanos , Hipertensão Induzida pela Gravidez/fisiopatologia , Óxido Nítrico/metabolismo , Gravidez , Transdução de Sinais/fisiologia
12.
Angiology ; 72(8): 776-786, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33678047

RESUMO

Platelets mediate circulating endothelial progenitor cell (EPC) recruitment and maturation, participating in vascular repair, however the underlying mechanism(s) remain unclear. We investigated the effect of platelet-rich plasma (PRP) on the functionality of CD34+-derived late-outgrowth endothelial cells (OECs) in culture. Confluent OECs were coincubated with PRP under platelet aggregation (with adenosine diphosphate; ADP) and nonaggregation conditions, in the presence/absence of the reversible P2Y12 platelet receptor antagonist ticagrelor. Outgrowth endothelial cell activation was evaluated by determining prostacyclin (PGI2) and monocyte chemoattractant protein-1 (MCP-1) release and intercellular adhesion molecule-1 (ICAM-1) membrane expression. Similar experiments were performed using human umbilical vein endothelial cells (HUVECs). Platelet-rich plasma increased ICAM-1 expression and PGI2 and MCP-1 secretion compared with autologous platelet-poor plasma, whereas ADP-aggregated platelets in PRP did not exhibit any effect. Platelet-rich plasma pretreated with ticagrelor prior to activation with ADP increased all markers to a similar extent as PRP. Similar results were obtained using HUVECs. In conclusion, PRP induces OEC activation, a phenomenon not observed when platelets are aggregated with ADP. Platelet inhibition with ticagrelor restores the PRP capability to activate OECs. Since EPC activation is important for endothelial regeneration and angiogenesis, we suggest that agents inhibiting platelet aggregation, such as ticagrelor, may promote platelet-EPC interaction and EPC function.


Assuntos
Plaquetas/metabolismo , Comunicação Celular , Células Progenitoras Endoteliais/metabolismo , Plasma Rico em Plaquetas/metabolismo , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Células Progenitoras Endoteliais/efeitos dos fármacos , Epoprostenol/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Plasma Rico em Plaquetas/efeitos dos fármacos , Ticagrelor/farmacologia
13.
Sci Adv ; 7(12)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33741600

RESUMO

Endothelial cyclooxygenase-1-derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.


Assuntos
Aterosclerose , Ciclo-Oxigenase 1/metabolismo , Epoprostenol , Proteínas de Membrana/metabolismo , Animais , Aterosclerose/etiologia , Ciclo-Oxigenase 1/genética , Epoprostenol/metabolismo , Camundongos , Prostaglandinas , Vasoconstrição
14.
Cardiovasc Res ; 117(9): 2001-2015, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-33484117

RESUMO

Arachidonic acid is one of the most abundant and ubiquitous ω-6 polyunsaturated fatty acid, present in esterified form in the membrane phospholipids of all mammalian cells and released from phospholipids by several phospholipases in response to various activating or inhibitory stimuli. Arachidonic acid is the precursor of a large number of enzymatically and non-enzymatically derived, biologically active autacoids, including prostaglandins (PGs), thromboxane (TX) A2, leukotrienes, and epoxyeicosatetraenoic acids (collectively called eicosanoids), endocannabinoids and isoprostanes, respectively. Eicosanoids are local modulators of the physiological functions and pathophysiological roles of blood vessels and platelets. For example, the importance of cyclooxygenase (COX)-1-derived TXA2 from activated platelets in contributing to primary haemostasis and atherothrombosis is demonstrated in animal and human models by the bleeding complications and cardioprotective effects associated with low-dose aspirin, a selective inhibitor of platelet COX-1. The relevance of vascular COX-2-derived prostacyclin (PGI2) in endothelial thromboresistance and atheroprotection is clearly shown by animal and human models and by the adverse cardiovascular effects exerted by COX-2 inhibitors in humans. A vast array of arachidonic acid-transforming enzymes, downstream synthases and isomerases, transmembrane receptors, and specificity in their tissue expression make arachidonic acid metabolism a fine-tuning system of vascular health and disease. Its pharmacological regulation is central in human cardiovascular diseases, as demonstrated by biochemical measurements and intervention trials.


Assuntos
Ácido Araquidônico/metabolismo , Aterosclerose/metabolismo , Plaquetas/metabolismo , Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Trombose/metabolismo , Tromboxano A2/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Fibrinolíticos/uso terapêutico , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais , Trombose/tratamento farmacológico , Trombose/fisiopatologia
15.
Expert Opin Pharmacother ; 22(1): 29-36, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32867545

RESUMO

INTRODUCTION: Selexipag is a first-in-class, oral, long-acting, selective, non-prostanoid agonist of the prostacyclin receptor (IP receptor), indicated for the treatment of symptomatic adult pulmonary arterial hypertension (PAH). It was designed with the objective to surpass the inconveniences associated with standard prostanoid therapy, presenting fewer adverse effects and comparable hemodynamic benefits. AREAS COVERED: This review describes the pharmacologic properties of selexipag and presents the clinical trials that have been completed or are currently ongoing regarding its clinical efficacy, safety, and tolerability. The pivotal GRIPHON study is extensively presented. EXPERT OPINION: Selexipag is the first IP receptor to reduce the morbidity/mortality composite endpoint of the GRIPHON study, a large, randomized, placebo-controlled study. The TRITON study failed to demonstrate a clear benefit of initial triple oral therapy including selexipag compared to initial double oral therapy. Current guidelines do not provide definitive recommendations regarding the place of selexipag in the treatment algorithm of PAH. Finally, the possibility of transition between the several drugs acting in the prostacyclin pathway, and the potential role of selexipag in chronic thromboembolic pulmonary hypertension and pediatric PAH is currently being examined, possibly expanding its future use.


Assuntos
Acetamidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirazinas/uso terapêutico , Administração Oral , Adulto , Epoprostenol/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
Drug Dev Res ; 82(2): 217-229, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32984987

RESUMO

Coronavirus disease 2019 (COVID 19) was first identified in Wuhan, China near the end of 2019. To date, COVID-19 had spread to almost 235 countries and territories due to its highly infectious nature. Moreover, there is no vaccine or Food and Drug Administration (FDA)-approved drug. More time is needed to establish one of them. Consequently, the drug repurposing approach seems to be the most attractive and quick solution to accommodate this crisis. In this regard, we performed molecular docking-based virtual screening of antiplatelet FDA-approved drugs on the key two viral target proteins: main protease (Mpro ) and spike glycoprotein (S) as potential inhibitor candidates for COVID-19. In the present study, 15 antiplatelet FDA-approved drugs were investigated against the concerned targets using the Molecular Docking Server. Our study revealed that only cilostazol has the most favorable binding interaction on Mpro (PDB ID: 6LU7) and cilostazol, iloprost, epoprostenol, prasugrel, and icosapent ethyl have a higher binding affinity on spike glycoprotein (S) (PDB ID: 6VYB) compared with recent anti-CoVID-19. Therefore, cilostazol is a promising FDA drug against COVID-19 by inhibiting both Mpro and S protein. The insights gained in this study may be useful for quick approach against COVID-19 in the future.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Cilostazol/metabolismo , Cilostazol/uso terapêutico , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/uso terapêutico , Epoprostenol/metabolismo , Epoprostenol/uso terapêutico , Humanos , Iloprosta/metabolismo , Iloprosta/uso terapêutico , Simulação de Acoplamento Molecular , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/metabolismo , Cloridrato de Prasugrel/uso terapêutico , Estados Unidos , United States Food and Drug Administration
17.
Pediatr Res ; 88(6): 850-856, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32927467

RESUMO

BACKGROUND: Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH. METHODS: Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity. RESULTS: Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p < 0.001) but not IGF1 (p = 0.13). CONCLUSIONS: Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension. IMPACT: Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology. There are few studies looking at the pathobiology of pulmonary hypertension only in children. The IGF axis is dysregulated in pediatric pulmonary arterial hypertension. IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension. IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.


Assuntos
Hipertensão Pulmonar/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/biossíntese , Adolescente , Asma/sangue , Asma/diagnóstico , Asma/mortalidade , Biomarcadores , Débito Cardíaco , Criança , Pré-Escolar , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Epoprostenol/metabolismo , Hemodinâmica , Humanos , Hipertensão Pulmonar/mortalidade , Lactente , Recém-Nascido , Pneumopatias , Miócitos Cardíacos/patologia , Prognóstico , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Resultado do Tratamento , Caminhada , Adulto Jovem
18.
Pharmacol Rev ; 72(4): 910-968, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32962984

RESUMO

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.


Assuntos
Receptores de Prostaglandina E/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Dinoprostona/imunologia , Dinoprostona/metabolismo , Epoprostenol/imunologia , Epoprostenol/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Polimorfismo de Nucleotídeo Único , Multimerização Proteica , Ratos , Receptores de Prostaglandina E/química , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/imunologia , Especificidade da Espécie
19.
J Am Heart Assoc ; 9(15): e016017, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32750305

RESUMO

BACKGROUND The mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects. METHODS AND RESULTS A total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand-grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (P<0.05) the remote vasodilator response to intra-arterial acetylcholine in the leg at 5 and 90 minutes after application. The enhanced response was associated with a 6-fold increase (P<0.05) in femoral venous plasma prostacyclin levels and with a transient increase (P<0.05) in arterial plasma levels of brain-derived neurotrophic factor and vascular endothelial growth factor. In contrast, hand-grip exercise did not influence remote microvascular function. CONCLUSIONS These findings demonstrate that ischemic preconditioning of the forearm improves remote microvascular endothelial function and suggest that one of the underlying mechanisms is a humoral-mediated potentiation of prostacyclin formation.


Assuntos
Endotélio Vascular/fisiologia , Epoprostenol/metabolismo , Precondicionamento Isquêmico , Microvasos/fisiologia , Circulação Sanguínea/fisiologia , Pressão Sanguínea/fisiologia , Artéria Braquial/metabolismo , Artéria Braquial/fisiologia , Endotélio Vascular/metabolismo , Exercício Físico/fisiologia , Feminino , Artéria Femoral/metabolismo , Artéria Femoral/fisiologia , Veia Femoral/metabolismo , Veia Femoral/fisiologia , Humanos , Masculino , Microvasos/metabolismo , Adulto Jovem
20.
Pharmacol Res ; 160: 105096, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32712319

RESUMO

The risk of thrombosis, a globally growing challenge and a major cause of death, is influenced by various factors in the intravascular coagulation, vessel wall, and cellular systems. Among the contributors to thrombosis, the contact activation system and the kallikrein/kinin system, two overlapping plasma proteolytic systems that are often considered as synonymous, regulate thrombosis from different aspects. On one hand, components of the contact activation system such as factor XII initiates activation of the coagulation proteins promoting thrombus formation on artificial surfaces through factor XI- and possibly prekallikrein-mediated intrinsic coagulation. On the other hand, physiological activation of plasma prekallikrein in the kallikrein/kinin system on endothelial cells liberates bradykinin from associated high-molecular-weight kininogen to stimulate the constitutive bradykinin B2 receptor to generate nitric oxide and prostacyclin to induce vasodilation and counterbalance angiotensin II signaling from the renin-angiotensin system which stimulates vasoconstriction. In addition to vascular tone regulation, this interaction between the kallikrein/kinin and renin-angiotensin systems has a thrombo-regulatory role independent of the contact pathway. At the level of the G-protein coupled receptors of these systems, defective bradykinin signaling due to attenuated bradykinin formation and/or decreased B2 receptor expression, as seen in murine prekallikrein and B2 receptor null mice, respectively, leads to compensatory overexpressed Mas, the receptor for angiotensin-(1-7) of the renin-angiotensin system. Mas stimulation and/or its increased expression contributes to maintaining a healthy vascular homeostasis by generating graded elevation of plasma prostacyclin which reduces thrombosis through two independent pathways: (1) increasing the vasoprotective transcription factor Sirtuin 1 to suppress tissue factor expression, and (2) inhibiting platelet activation. This review will summarize the recent advances in this field that support these understandings. Appreciating these subtle mechanisms help to develop novel anti-thrombotic strategies by targeting the vascular receptors in the renin-angiotensin and the kallikrein/kinin systems to maintain healthy vascular homeostasis.


Assuntos
Coagulação Sanguínea , Sistema Calicreína-Cinina/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina , Trombose/sangue , Animais , Epoprostenol/metabolismo , Humanos , Pré-Calicreína/metabolismo , Receptor B2 da Bradicinina/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo
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