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1.
Int J Nanomedicine ; 16: 1377-1390, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658778

RESUMEN

Background: Vascular drug delivery becomes a promising direction in the development of novel therapeutic strategies in the treatment of cardiovascular pathologies, such as hypertension. However, targeted delivery of hydrophobic substances, with poor bioavailability, remains a challenge. Here, we described the hypotensive effects of a low dose of curcumin delivered to the vascular wall using hyaluronic acid-based nanocapsules. Methods: The group of hypertensive TGR(m-Ren2)27 rats, was administrated respectively with the vehicle, curcumin solution or curcumin delivered using hyaluronic acid-based nanocapsules (HyC12-Cur), for 7 days each, maintaining the wash-out period between treatments. Arterial blood pressure (systolic - SBP, diastolic - DBP) and heart rate (HR) were monitored continuously using a telemetry system (Data Science International), and Mean Arterial Pressure (MAP) was calculated from SBP and DBP. Results: In hypertensive rats, a low dose of curcumin (4.5 mg/kg) administrated in HyC12-Cur for 7 days resulted in a gradual inhibition of SBP, DBP and MAP increase without an effect on HR. At the end of HyC12-Cur - based treatment changes in SBP, DBP and MAP amounted to -2.0±0.8 mmHg, -3.9±0.7 mmHg and -3.3±0.7 mmHg, respectively. In contrast, the administration of a curcumin solution (4.5 mg/kg) did not result in a significant hypotensive effect and the animals constantly developed hypertension. Vascular delivery of capsules with curcumin was confirmed using newly developed fluorine-rich nanocapsules (HyFC10-PFOB) with a shell based on a HA derivative and similar size as HyC12-Cur. HyFC10-PFOB gave fluorine signals in rat aortas analyzed ex vivo with a 19F NMR technique after a single intragastric administration. Conclusion: These results suggest that nanocapsules based on hyaluronic acid, the ubiquitous glycosaminoglycan of the extracellular matrix and an integral part of endothelial glycocalyx, may represent a suitable approach to deliver hydrophobic, poorly bioavailable compounds, to the vascular wall.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/uso terapéutico , Ácido Hialurónico/química , Hipertensión/tratamiento farmacológico , Nanocápsulas/química , Administración Oral , Animales , Aorta/efectos de los fármacos , Aorta/patología , Presión Sanguínea/efectos de los fármacos , Curcumina/farmacología , Diástole/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Flúor/química , Frecuencia Cardíaca/efectos de los fármacos , Hidrodinámica , Interacciones Hidrofóbicas e Hidrofílicas , Hipertensión/fisiopatología , Espectroscopía de Resonancia Magnética , Masculino , Tamaño de la Partícula , Ratas , Electricidad Estática , Sístole/efectos de los fármacos
2.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-33467058

RESUMEN

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H2O2 release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions.


Asunto(s)
Difosfonatos/farmacología , Naftalenosulfonatos/farmacología , Agonistas del Receptor Purinérgico P2/farmacología , Receptores Purinérgicos P2/metabolismo , Daño por Reperfusión/metabolismo , Túnica Íntima/patología , Angiotensina II/toxicidad , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Difosfonatos/uso terapéutico , Endotelina-1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hiperplasia/prevención & control , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Naftalenosulfonatos/uso terapéutico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Agonistas del Receptor Purinérgico P2/uso terapéutico , Ratas , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológico , Túnica Íntima/efectos de los fármacos , Túnica Íntima/metabolismo , Vasodilatación , Agua/metabolismo
3.
Biochem Biophys Res Commun ; 534: 67-72, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33310190

RESUMEN

Cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, is a target of thalidomide and thalidomide-derived immunomodulatory drugs (IMiDs). The binding of these IMiDs to CRBN alters the substrate specificity of the ligase, thereby mediating multiple effects that are exploited in cancer therapy. However, to date, it is not clear which other possible targets might be involved in the efficacy of IMiDs. One especially prominent effect of a number of thalidomide analogs is their ability to inhibit angiogenesis, which is typically enhanced in fluorinated analogs. So far, the involvement of CRBN in antiangiogenic effects is under debate. Here, starting from a systematic set of thalidomide analogs and employing a quantitative in vitro CRBN-binding assay, we study the correlation of fluorination, CRBN binding and antiangiogenic effects. We clearly identify fluorination to correlate both with CRBN binding affinity and with antiangiogenic effects, but do not find a correlation between the latter two phenomena, indicating that the main target for the antiangiogenic effects of thalidomide analogs still remains to be identified.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Inhibidores de la Angiogénesis/farmacología , Factores Inmunológicos/metabolismo , Factores Inmunológicos/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Inhibidores de la Angiogénesis/química , Animales , Aorta/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Halogenación , Células Endoteliales de la Vena Umbilical Humana , Humanos , Factores Inmunológicos/química , Masculino , Ratas Sprague-Dawley , Relación Estructura-Actividad , Talidomida/análogos & derivados
4.
J Ethnopharmacol ; 266: 113453, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33039628

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Baizhu Tianma decoction (BBTD) is a classical representative prescription for expelling phlegm, extinguishing wind, strengthening the spleen and dissipating excessive fluid in traditional Chinese medicine (TCM). According to both TCM theory and about 300 years of clinical practice, BBTD is especially suitable for hypertensive patients of abdominal obesity and lacking physical activity. AIM OF THE STUDY: The present study tried to interpret the pharmacology of the ancient formula of BBTD. Herein, we focused on the plasma metabonomics of BBTD and evaluated the effect and targets of BBTD on endothelial protective effect. METHODS: Obesity-related hypertensive mice were induced by high-fat diet for 20 weeks. BBTD (17.8 g/kg) was administered intragastrically for 8 weeks, and telmisartan group (12.5 mg/kg) was used as positive drug. Body weight, blood pressure, triglyceride and cholesterol were recorded to evaluate the efficacy of BBTD in vivo. Lipid deposition in aortic roots was assessed by oil red O staining, while morphology of aortas was observed by HE staining. Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed to study the plasma non-targeted metabonomics. According to the data of metabonomics, human aortic endothelial cells (HAECs) were treated by oxidized low-density lipoprotein (ox-LDL, 50 µg/mL) with/without BBTD (2, 1 or 0.5 mg/mL). Apoptosis rate (Annexin V-FITC/PI), migration (Transwell), cytoskeleton (Phalloidin) and density of VE-cadherin (Immunofluorescence staining) were used to investigate the effect of BBTD in vitro. Transcriptome sequencing was performed (2 mg/mL BBTD vs ox-LDL) to screen the possible targets of BBTD in endothelial protection against ox-LDL. RESULTS: BBTD effectively reduced the body weight and total cholesterol, and decreased 12.1 mmHg in SBP and 10.5 mmHg in DBP of obesity-related hypertensive mice (P < 0.05). BBTD attenuated lipid deposition in arterial roots and improved the morphology of aortas in vivo. Plasma metabolite profiles identified 94 differential metabolites and suggested BBTD mainly affected glycerophospholipids and fatty acyls. Bioinformatics analysis indicated sphingolipid metabolism and fluid shear stress and atherosclerosis were main pathways. Therefore, we focused on endothelial protective effect of BBTD against ox-LDL. In vitro, BBTD demonstrated endothelial protective effects, decreasing apoptosis rate, improving cell migration in dose-dependent manner and maintaining cell morphology. Transcriptome sequencing identified 251 downregulated and 603 upregulated mRNAs after 24h-BBTD treatment, which reversed 51.8% change in mRNAs (393 DE mRNAs) induced by ox-LDL. Bioinformatics analysis supported the potential of BBTD in hypertension and suggested that BBTD improved endothelial cells by targeting mainly on p53 and PPAR signaling pathways. CONCLUSIONS: BBTD attenuates obesity-related hypertension by regulating metabolism of glycerophospholipids and endothelial protection.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Hipertensión/tratamiento farmacológico , Metabolómica , Obesidad/prevención & control , Animales , Aorta/citología , Aorta/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Hipertensión/complicaciones , Hipertensión/metabolismo , Lipoproteínas LDL/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo
5.
Phytomedicine ; 81: 153430, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33341451

RESUMEN

BACKGROUND: Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. PURPOSE: The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque. METHODS: Differentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks. RESULTS: Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner. CONCLUSION: Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Azepinas/farmacología , Endotelio Vascular/efectos de los fármacos , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Lactonas/farmacología , Piperidinas/farmacología , Sustancias Protectoras/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aterosclerosis/metabolismo , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , FN-kappa B/metabolismo , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Vasodilatación/efectos de los fármacos
6.
Molecules ; 25(24)2020 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-33322104

RESUMEN

Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.


Asunto(s)
Alprostadil/análogos & derivados , Alprostadil/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Metabolómica , Óxido Nítrico/antagonistas & inhibidores , Alprostadil/sangre , Animales , Antiinflamatorios no Esteroideos/química , Aorta/efectos de los fármacos , Aorta/metabolismo , Cromatografía Liquida , Humanos , Espectrometría de Masas , Redes y Vías Metabólicas , Metabolómica/métodos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Óxido Nítrico/biosíntesis , Enfermedad Arterial Periférica/tratamiento farmacológico , Conejos
7.
Mar Drugs ; 18(12)2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33339328

RESUMEN

In hyperlipidemia, pyroptosis in endothelial cells (ECs) induces atherosclerosis via the toll-like receptor 4 (TLR4) pathway. We evaluated the effects of Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB) on pyroptosis of ECs and vascular smooth muscle cells (VSMCs), which leads to attenuation of these cells and dysfunction of the aorta in high-fat-diet (HFD)-fed mice and in palmitate-treated ECs and VSMCs. The expression of TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which induce formation of NOD-LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasomes, were increased by HFD and were decreased by ECE and PPB. The TLR4/NF-κB pathway was upregulated in palmitate-treated ECs and VSMCs and was decreased by ECE and PPB. The expressions of NLRP3/apoptosis-associated speck like protein containing a caspase recruitment domain, caspase-1, interleukin (IL)-1ß, and IL-18 were increased by HFD and were decreased by ECE and PPB. Pyroptotic cells were increased by HFD and decreased by ECE and PPB. The expressions of the adhesion molecules, intercellular adhesion molecule and vascular cell adhesion molecule, and endothelin-1 were increased by HFD and were decreased by ECE and PPB. ECE and PPB decreased pyroptosis in the ECs and VSMCs, which was induced by HFD in the mouse aorta, and attenuated EC and VSMC dysfunction, an initiation factor of atherosclerosis.


Asunto(s)
Aorta/efectos de los fármacos , Benzofuranos/farmacología , Dieta Alta en Grasa , Células Endoteliales/efectos de los fármacos , Hipolipemiantes/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Piroptosis , Taninos/farmacología , Anciano , Animales , Aorta/citología , Células Cultivadas , Humanos , Recién Nacido , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR/biosíntesis , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Palmitatos/farmacología , Receptor Toll-Like 4/biosíntesis , Receptor Toll-Like 4/genética , Cicatrización de Heridas/efectos de los fármacos
8.
Phytomedicine ; 79: 153325, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32920289

RESUMEN

BACKGROUND: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury. PURPOSE: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction. STUDY DESIGN/METHODS: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings. RESULTS: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction. CONCLUSION: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.


Asunto(s)
Endotelio Vascular/efectos de los fármacos , Ginsenósidos/farmacología , Nicotina/toxicidad , Angiotensina II/sangre , Angiotensina II/metabolismo , Animales , Aorta/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Ginsenósidos/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Masculino , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/sangre , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenilefrina/farmacología , Agregación Plaquetaria/efectos de los fármacos , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Receptor Toll-Like 4/metabolismo , Triterpenos/química , Vasoconstricción/efectos de los fármacos
9.
Phytomedicine ; 78: 153302, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32823242

RESUMEN

BACKGROUND: Therapeutic angiogenesis is a novel strategy for the treatment of ischemic diseases that involves promotion of angiogenesis in ischemic tissues via the use of proangiogenic agents. However, effective proangiogenic drugs that activate the Ang2/Tie2 signaling pathway remain scarce. PURPOSE: We aimed to investigate the proangiogenic activity of notoginsenoside R1 (NR1) isolated from total saponins of Panax notoginseng with regard to activation of the Ang2/Tie2 signaling pathway. METHODS: We examined the proangiogenic effects of NR1 by assessing the effects of NR1 on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). The aortic ring assay and vascular endothelial growth factor receptor inhibitor (VRI)-induced vascular regression in the zebrafish model were used to confirm the proangiogenic effects of NR1 ex vivo and in vivo. Furthermore, the molecular mechanism was investigated by Western blot analysis. RESULTS: We found that NR1 promoted the proliferation, mobility and tube formation of HUVECs in vitro. NR1 also increased the number of sprouting vessels in rat aortic rings and rescued VRI-induced vascular regression in zebrafish. NR1-induced angiogenesis was dependent on Tie2 receptor activation mediated by increased autocrine Ang2 in HUVECs, and inhibition of the Ang2/Tie2 pathway abrogated the proangiogenic effects of NR1. CONCLUSIONS: Our results suggest that NR1 promotes angiogenesis by activating the Ang2/Tie2 signaling pathway. Thus, NR1-induced activation of the Ang2/Tie2 pathway is an effective proangiogenic approach. NR1 may be useful agent for the treatment of ischemic diseases.


Asunto(s)
Angiopoyetina 2/metabolismo , Ginsenósidos/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Receptor TIE-2/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Axitinib/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neovascularización Fisiológica/fisiología , Panax notoginseng/química , Ratas Sprague-Dawley , Pez Cebra/embriología
10.
Toxicol Lett ; 333: 80-89, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32738273

RESUMEN

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin-angiotensin system and COX2 pathway activation.


Asunto(s)
Cloruro de Cadmio/toxicidad , Ciclooxigenasa 2/metabolismo , Endotelio Vascular/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Hipertensión/inducido químicamente , NADPH Oxidasas/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Presión Sanguínea/efectos de los fármacos , Cloruro de Cadmio/sangre , Relación Dosis-Respuesta a Droga , Endotelio Vascular/enzimología , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Contaminantes Ambientales/sangre , Hipertensión/enzimología , Hipertensión/patología , Hipertensión/fisiopatología , Inyecciones Intraperitoneales , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/enzimología , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de Señal , Vasoconstricción/efectos de los fármacos
11.
Sci Rep ; 10(1): 12220, 2020 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-32699285

RESUMEN

Growing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC50). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs.


Asunto(s)
Acetaldehído/análogos & derivados , Aorta/metabolismo , Aorta/fisiopatología , Presión Sanguínea/fisiología , Corazón/fisiopatología , Remodelación Vascular/fisiología , Acetaldehído/metabolismo , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Colágeno/metabolismo , GMP Cíclico/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Productos Finales de Glicación Avanzada/metabolismo , Corazón/efectos de los fármacos , Masculino , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Remodelación Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología
12.
High Blood Press Cardiovasc Prev ; 27(4): 299-308, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32572706

RESUMEN

Large conductive arteries undergo to structural modifications by aging, eventually leading to increased vascular stiffness. As consequence, cardiovascular hemodynamic changes by increasing central blood pressure which may be also associated to the remodelling of peripheral resistance arteries that contribute to increase further the central vascular stiffness and blood pressure. These modifications resemble the ones that has been shown in essential hypertension, thus a condition of "early vascular aging" has been described in hypertensive patients. Since hypertension related target organs, particularly the heart, face aortic blood pressure rather than brachial blood pressure, it has been recently suggested that central blood pressure and other parameters of large arteries' stiffness, including pulse wave velocity (PWV), may better correlate with subclinical organ damage and might be useful to assess the cardiovascular risk of patients beyond the traditional risk factors. Different devices have been validated to measure central blood pressure and PWV, and are currently available for clinical use. The increasing application of these tools in clinical practice could improve the management of hypertensive patients by better defining the cardiovascular risk and address the antihypertensive therapy.


Asunto(s)
Envejecimiento , Aorta/fisiopatología , Presión Arterial , Hipertensión/fisiopatología , Remodelación Vascular , Rigidez Vascular , Factores de Edad , Animales , Antihipertensivos/uso terapéutico , Aorta/efectos de los fármacos , Presión Arterial/efectos de los fármacos , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Pronóstico , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Remodelación Vascular/efectos de los fármacos , Rigidez Vascular/efectos de los fármacos
13.
Nanotoxicology ; 14(8): 1017-1038, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32574508

RESUMEN

Nanomaterials (NMs) with tubular structures, such as halloysite nanotubes (HNTs), have potential applications in biomedicine. Although the biocompatibility of HNTs has been investigated before, the toxicity of HNTs to blood vessels is rarely systemically evaluated. Herein, we compared the toxicity of HNTs and multi-walled carbon nanotubes (MWCNTs) to human umbilical vein endothelial cells (HUVECs) in vitro and blood vessels of mice in vivo. HUVECs internalized HNTs and MWCNTs, but the uptake of HNTs was not obviously changed by clathrin inhibitor. Exposure to NMs decreased cellular viability, activated apoptotic proteins and up-regulated adhesion molecules, including soluble vascular cell adhesion molecule 1 (sVCAM-1) and VCAM-1. As the mechanisms, NMs decreased NO levels, eNOS mRNA and eNOS/p-eNOS proteins. Meanwhile, NMs promoted intracellular ROS and autophagy dysfunction, shown as decreased protein levels of LC3, beclin-1 and ATG5. The eNOS regulator Kruppel-like factor 4 (KLF4) was inhibited, but another eNOS regulator KLF4 was surprisingly up-regulated. Under in vivo conditions, ICR mice intravenously injected with NMs (50 µg/mouse, once a day for 5 days) showed an increased percentage of neutrophils, monocytes and basophils. Meanwhile, autophagy dysfunction, eNOS uncoupling, activation of apoptotic proteins and alteration of KLF proteins were also observed in mouse aortas. All of the toxic effects were more pronounced for MWCNTs in comparison with HNTs based on the same mass concentrations. Our results may provide novel insights about the toxicity of NMs with tubular structures to blood vessels. Considering the toxicological data reported here, HNTs are probably safer nanocarriers compared with MWCNTs.


Asunto(s)
Aorta/efectos de los fármacos , Arcilla/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Nanotubos/toxicidad , Animales , Aorta/metabolismo , Aorta/patología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Recuento de Células Sanguíneas , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Endogámicos ICR , Nanotubos/química , Nanotubos de Carbono/química , Óxido Nítrico Sintasa de Tipo III/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo
14.
Cardiovasc Pathol ; 49: 107230, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32585603

RESUMEN

PURPOSE: Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism. METHODS: Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg.kg-1.d-1olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ. RESULTS: After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect. CONCLUSION: Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Receptores de Apelina/metabolismo , Apelina/metabolismo , Imidazoles/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Neointima , Tetrazoles/farmacología , Lesiones del Sistema Vascular/tratamiento farmacológico , Angioplastia de Balón , Angiotensina II/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/lesiones , Aorta/metabolismo , Aorta/patología , Proliferación Celular/efectos de los fármacos , Constricción Patológica , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Músculo Liso Vascular/lesiones , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Fosforilación , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal , Lesiones del Sistema Vascular/etiología , Lesiones del Sistema Vascular/metabolismo , Lesiones del Sistema Vascular/patología
15.
Toxicol Appl Pharmacol ; 400: 115070, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32464219

RESUMEN

Vascular dysfunction plays a critical role in the pathogenesis of sepsis. We elucidated the mechanisms underlying the amelioration of lipopolysaccharide (LPS)-induced vascular inflammation by oroxylin A (OroA) post-treatment in rats. The animals were intraperitoneally injected with LPS (10 mg/kg) to induce systemic inflammation and intravenously (iv) administered OroA (15 mg/kg) 6 h after the LPS treatment. The assessments included biochemical changes in peripheral blood, vascular reactivity which was evaluated by blood-vessel myography, morphological/histological assessment of inflammation, toll-like receptor (TLR)-4-mediated interleukin-1-receptor-associated-kinase (IRAK)-4 activation, changes in adhesion molecule expression, and endothelial junctional stability in the aorta. LPS significantly enhanced the proinflammatory cytokine release, increased vascular cell adhesion molecule (VCAM)-1 expression, disrupted endothelial tight junction, reduced vascular endothelial barrier stability, and increased macrophage infiltration and accumulation in the aorta. All observed pathological changes and vascular inflammation were significantly reversed by the OroA post-treatment. Importantly, OroA suppressed the increased adhesion molecule expression and the endothelial barrier disruption by inhibiting LPS-activated IRAK-4-targeted inhibitory nuclear factor kappa B kinase (IKK) α/ß complex phosphorylation, without directly affecting the interaction between LPS and TLR-4. Moreover, the iNOS activity induced by the LPS challenge was inhibited by the OroA pretreatment of the isolated aortic rings. These results suggest that OroA regulates the vascular tone by inhibiting vascular hyporeactivity caused by NO overproduction and reverses the endothelial barrier dysfunction and inflammation by inhibiting the IRAK-4-mediated IKKα/ß phosphorylation. Overall, these findings suggest OroA administration as a potentially useful therapeutic approach for clinical interventions in septic shock.


Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Flavonoides/farmacología , Sepsis/prevención & control , Molécula 1 de Adhesión Celular Vascular/genética , Animales , Aorta/inmunología , Aorta/patología , Células Cultivadas , Quimiocina CCL2/sangre , Citocinas/sangre , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Endotoxinas/farmacología , Flavonoides/uso terapéutico , Expresión Génica/efectos de los fármacos , Masculino , Infiltración Neutrófila/efectos de los fármacos , Ratas Sprague-Dawley , Sepsis/sangre , Sepsis/patología
16.
Toxicol Appl Pharmacol ; 400: 115041, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32428593

RESUMEN

Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Materiales de Construcción/toxicidad , Polvo/análisis , Endotelio Vascular/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Neumonía/inducido químicamente , Contaminantes Atmosféricos/análisis , Animales , Aorta/efectos de los fármacos , Aorta/fisiopatología , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Materiales de Construcción/análisis , Endotelio Vascular/fisiopatología , Humanos , Exposición por Inhalación/análisis , Pulmón/efectos de los fármacos , Pulmón/inmunología , Ratones Endogámicos C57BL , Cavidad Nasal/efectos de los fármacos , Cavidad Nasal/inmunología , Ciudad de Nueva York , Ataques Terroristas del 11 de Septiembre , Células THP-1
17.
Nat Commun ; 11(1): 2622, 2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-32457361

RESUMEN

Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Citocinas/metabolismo , Sistemas de Liberación de Medicamentos , Macrófagos/metabolismo , Nanopartículas/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aterosclerosis/metabolismo , Atorvastatina/uso terapéutico , Materiales Biomiméticos , Membrana Celular/metabolismo , Liberación de Fármacos , Femenino , Ratones , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Resultado del Tratamiento
18.
Arterioscler Thromb Vasc Biol ; 40(6): 1559-1573, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32321307

RESUMEN

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-ß-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.


Asunto(s)
Aneurisma de la Aorta Abdominal/etiología , Inflamación/etiología , Músculo Liso Vascular/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/fisiología , Transducción de Señal/fisiología , Angiotensina II/administración & dosificación , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aneurisma de la Aorta Abdominal/patología , Cloruro de Calcio/administración & dosificación , Expresión Génica , Regulación de la Expresión Génica/fisiología , Humanos , Interleucina-6/genética , Macrófagos/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Ratones Transgénicos , Monocitos/patología , Músculo Liso Vascular/química , Miocitos del Músculo Liso/metabolismo , Proteína-Lisina 6-Oxidasa/análisis , Proteína-Lisina 6-Oxidasa/genética , Receptores de Citocinas/genética , Subtipo EP4 de Receptores de Prostaglandina E/genética
19.
Cardiovasc Ther ; 2020: 1926249, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32328171

RESUMEN

Isoliquiritigenin (ISL) is a flavonoid isolated mainly from the licorice plant, a traditional Chinese herb. ISL has shown anticancer, anti-inflammatory, antioxidant, and antidiabetic activities. However, the pharmaceutical effects of ISL on atherosclerosis are seldom explored. In this study, we used apolipoprotein E (ApoE) knockout mouse model and angiotensin II- (Ang II-) stimulated vascular smooth muscle cells (VSMCs) to elucidate the pharmacological mechanism of ISL to inhibit atherosclerosis. We found that in ApoE-/- mice ISL could attenuate atherosclerotic lesion, reduce serum lipid levels, and inhibit TRPC5 expression. In vitro, ISL inhibited Ang II-stimulated proliferation of VSMCs and suppressed Ang II-induced TRPC5 and PCNA expressions in a dose-dependent fashion. In conclusion, our findings provide novel insight into the pharmacological effects of ISL on atherosclerosis and suggest that ISL is beneficial for cardiovascular protection.


Asunto(s)
Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Chalconas/farmacología , Placa Aterosclerótica , Canales Catiónicos TRPC/antagonistas & inhibidores , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Lípidos/sangre , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Transducción de Señal , Canales Catiónicos TRPC/metabolismo
20.
Am J Physiol Heart Circ Physiol ; 318(5): H1346-H1355, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32302491

RESUMEN

Renovascular hypertension is characterized by activation of the renin-angiotensin-aldosterone system, blunted natriuretic responses, and elevated sympathetic nerve activity. Excess dietary salt intake exaggerates arterial blood pressure (ABP) in multiple models of experimental hypertension. The present study tested whether a high-salt diet exaggerated ABP and vascular dysfunction in a 2-kidney, 1-clip (2K1C) murine model. Male C57BL/6J mice (8-12 wk) were randomly assigned, and fed a 0.1% or 4.0% NaCl diet, and instrumented with telemetry units to measure ABP. Then, the 2K1C model was produced by placing a cuff around the right renal artery. Systolic, diastolic, and mean ABP were significantly higher in mice fed 4.0% vs. 0.1% NaCl at 1 wk but not after 3 wk. Interestingly, 2K1C hypertension progressively increased arterial pulse pressure in both groups; however, the magnitude was significantly greater in mice fed 4.0% vs. 0.1% NaCl at 3 wk. Moreover, pulse wave velocity was significantly greater in 2K1C mice fed 4.0% vs. 0.1% NaCl diet or sham-operated mice fed either diet. Histological assessment of aortas indicated no structural differences among groups. Finally, endothelium-dependent vasodilation was significantly and selectively attenuated in the aorta but not mesenteric arteries of 2K1C mice fed 4.0% NaCl vs. 0.1% NaCl or sham-operated control mice. The findings suggest that dietary salt loading transiently exaggerates 2K1C renovascular hypertension but promotes chronic aortic stiffness and selective aortic vascular dysfunction.NEW & NOTEWORTHY High dietary salt exaggerates hypertension in multiple experimental models. Here we demonstrate that a high-salt diet produces a greater increase in arterial blood pressure at 1 wk after induction of 2-kidney, 1-clip (2K1C) hypertension but not at 3 wk. Interestingly, 2K1C mice fed a high-salt diet displayed an exaggerated pulse pressure, elevated pulse wave velocity, and reduced endothelium-dependent vasodilation of the aorta but not mesenteric arteries. These findings suggest that dietary salt may interact with underlying cardiovascular disease to promote selective vascular dysfunction and aortic stiffness.


Asunto(s)
Hipertensión Renovascular/etiología , Cloruro de Sodio Dietético/efectos adversos , Rigidez Vascular , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Presión Sanguínea , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Cloruro de Sodio Dietético/toxicidad , Vasoconstricción
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