RESUMEN
The intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in atherosclerosis pathogenesis. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. Here, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima. Partial ligation of the left carotid artery (LCA) was performed in C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected 2 days and 2 weeks after surgery to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. The chronic effects of d-flow were decoupled from the ensuing arterial wall stiffening by administration of ß-aminopropionitrile (BAPN), an inhibitor of collagen crosslinking by lysyl oxidase (LOX) enzymes. Atomic force microscopy (AFM) was used to determine stiffness of the endothelium and the denuded subendothelial matrix in en face carotid preparations. The stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels was also determined. Acute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. In addition, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels. We conclude that chronic d-flow results in marked stiffening of the arterial intima, which can be effectively prevented by inhibition of collagen crosslinking.
Asunto(s)
Arterias Carótidas , Ratones Endogámicos C57BL , Rigidez Vascular , Animales , Masculino , Rigidez Vascular/efectos de los fármacos , Ratones , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Arterias Carótidas/fisiopatología , Femenino , Túnica Íntima/patología , Túnica Íntima/efectos de los fármacos , Colágeno/metabolismo , Aminopropionitrilo/farmacología , Proteína-Lisina 6-Oxidasa/metabolismo , Proteína-Lisina 6-Oxidasa/antagonistas & inhibidores , Microscopía de Fuerza Atómica , Humanos , Estrés Mecánico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismoRESUMEN
BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
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Modelos Animales de Enfermedad , Ratones Noqueados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Receptores de Tipo II del Péptido Intestinal Vasoactivo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/genética , Ratones , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Hiperalgesia/fisiopatología , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ratones Endogámicos C57BL , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Miembro Posterior/fisiopatologíaRESUMEN
BACKGROUND: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration. METHODS AND RESULTS: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca2+ activated K+ BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes. CONCLUSIONS: Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Ratones Endogámicos C57BL , Estrés Oxidativo , Pravastatina , Animales , Pravastatina/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/efectos de la radiación , Vasodilatación/efectos de los fármacos , Vasodilatación/efectos de la radiación , Masculino , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Transcripción ReIA/metabolismo , NADPH Oxidasas/metabolismo , Ratones , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Esquema de Medicación , Arterias Carótidas/efectos de la radiación , Arterias Carótidas/efectos de los fármacos , Enfermedad Crónica , Modelos Animales de Enfermedad , NADPH Oxidasa 4RESUMEN
Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.
Asunto(s)
Clopidogrel , Citocromo P-450 CYP2C19 , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Stents , Humanos , Citocromo P-450 CYP2C19/genética , Clopidogrel/uso terapéutico , Clopidogrel/farmacología , Clopidogrel/farmacocinética , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/farmacocinética , Masculino , Femenino , Agregación Plaquetaria/efectos de los fármacos , Anciano , Persona de Mediana Edad , Polimorfismo Genético , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Ticlopidina/farmacología , Genotipo , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/cirugíaRESUMEN
Decellularized vascular tissue has high potential as a tissue-engineered vascular graft because of its similarity to native vessels in terms of mechanical strength. However, exposed collagen on the tissue induces blood coagulation, and low hemocompatibility is a major obstacle to its vascular application. Here we report that freeze-drying and ethanol treatment effectively modify collagen fiber structure and drastically reduce blood coagulation on the graft surface without exogenous chemical modification. Decellularized carotid artery of ostrich was treated with freeze-drying and ethanol solution at concentrations ranging between 5 and 99.5 %. Collagen fiber distance in the graft was narrowed by freeze-drying, and the non-helical region increased by ethanol treatment. Although in vitro blood coagulation pattern was similar on the grafts, platelet adhesion on the grafts was largely suppressed by freeze-drying and ethanol treatments. Ex vivo blood circulation tests also indicated that the adsorption of platelets and Von Willebrand Factor was largely reduced to approximately 80 % by ethanol treatment. These results indicate that structural modification of collagen fibers in decellularized tissue reduces blood coagulation on the surface by inhibiting platelet adhesion.
Asunto(s)
Coagulación Sanguínea , Colágeno , Adhesividad Plaquetaria , Animales , Adhesividad Plaquetaria/efectos de los fármacos , Coagulación Sanguínea/efectos de los fármacos , Colágeno/química , Ingeniería de Tejidos/métodos , Ensayo de Materiales , Liofilización , Prótesis Vascular , Andamios del Tejido/química , Plaquetas/metabolismo , Plaquetas/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Arterias Carótidas/efectos de los fármacos , Humanos , Etanol/químicaRESUMEN
Hypotension induced by general anesthesia is associated with postoperative complications, increased mortality, and morbidity, particularly elderly patients. The aim of this study was to investigate the effectiveness of corrected carotid artery flow time (FTc) for predicting hypotension following anesthesia induction in patients over 65 years old. After faculty ethical committee approval and written informed consent, 138 patients (65 years and older, ASA physical status I-III) who scheduled for elective surgery were included in this study. In the pre-operative anesthesia unit, the carotid artery FTc value was measured by ultrasound and hemodynamic values were recorded. Following anesthesia induction with propofol, hemodynamic data were recorded at 1-minute intervals for 3 min. Measurements were terminated prior to endotracheal intubation, as direct laryngoscopy and endotracheal intubation could cause sympathetic stimulation and hemodynamic changes. Hypotension occurred in 52 patients (37.7%). The preoperative FTc value of the patients who developed hypotension was statistically lower (312.5 ms) than the patients who did not (345.0 ms) (p < 0.001). The area under the ROC curve for carotid artery FTc was 0.93 (95% CI for AUC:0.89-0.97; p < 0.001) with an optimal cut-off of value for predicting post-anesthesia hypotension 333 ms, a sensitivity of 90.4% and a specificity of 84.9%. As a result of the multiple logistic regression model, carotid artery FTc emerged as the sole independent risk factor for hypotension following anesthesia induction. Preoperative carotid artery FTc measurement is a simple, bedside, noninvasive, and reliable method for predicting anesthesia-induced hypotension in elderly patients.
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Tiempo de Circulación Sanguínea , Arterias Carótidas , Hipotensión , Propofol , Arterias Carótidas/efectos de los fármacos , Hipotensión/inducido químicamente , Hipotensión/diagnóstico , Valor Predictivo de las Pruebas , Propofol/farmacología , Humanos , Masculino , Femenino , Anciano , Modelos Logísticos , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation and phenotypic switching are key mechanisms in the development of proliferative arterial diseases. Notably, reprogramming of the glucose metabolism pattern in VSMCs plays an important role in this process. PURPOSE: The aim of this study is to investigate the therapeutic potential and the mechanism underlying the effect of bergenin, an active compound found in Bergenia, in proliferative arterial diseases. METHODS: The effect of bergenin on proliferative arterial disease was evaluated using platelet-derived growth factor (PDGF)-stimulated VSMCs and a mouse model of carotid artery ligation. VSMC proliferation and phenotypic switching were evaluated in vitro using cell counting kit-8, 5-ethynyl-2-deoxyuridine incorporation, scratch, and transwell assays. Carotid artery neointimal hyperplasia was evaluated in vivo using hematoxylin and eosin staining and immunofluorescence. The expression of proliferation and VSMC contractile phenotype markers was evaluated using PCR and western blotting. RESULTS: Bergenin treatment inhibited PDGF-induced VSMC proliferation and phenotypic switching and reduced neointimal hyperplasia in the carotid artery ligation model. Additionally, bergenin partially reversed the PDGF-induced Warburg-like glucose metabolism pattern in VSMCs. RNA-sequencing data revealed that bergenin treatment significantly upregulated Ndufs2, an essential subunit of mitochondrial complex I. Ndufs2 knockdown attenuated the inhibitory effect of bergenin on PDGF-induced VSMC proliferation and phenotypic switching, and suppressed neointimal hyperplasia in vivo. Conversely, Ndufs2 overexpression enhanced the protective effect of bergenin. Moreover, Ndufs2 knockdown abrogated the effects of bergenin on the regulation of glucose metabolism in VSMCs. CONCLUSION: These findings suggest that bergenin is effective in alleviating proliferative arterial diseases. The reversal of the Warburg-like glucose metabolism pattern in VSMCs during proliferation and phenotypic switching may underlie this therapeutic mechanism.
Asunto(s)
Benzopiranos , Proliferación Celular , Glucosa , Músculo Liso Vascular , Animales , Músculo Liso Vascular/efectos de los fármacos , Glucosa/metabolismo , Benzopiranos/farmacología , Proliferación Celular/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Derivado de Plaquetas/farmacología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Modelos Animales de Enfermedad , Células Cultivadas , Arterias Carótidas/efectos de los fármacos , Neointima/tratamiento farmacológicoRESUMEN
Endothelium-dependent contraction (EDC) exists in blood vessels of normotensive animals, but is exaggerated in hypertension. An early signal in EDC is cytosolic Ca2+ rise in endothelial cells. In this study we investigated the functional role of Orai1, a major endothelial cell Ca2+ entry channel, in EDC. Hypertension model was established in WT mice by intake of L-NNA in the drinking water (0.5 g/L) for 4 weeks or osmotic pump delivery of Ang II (1.5 mg·kg-1·d-1) for 2 weeks. In TRPC5 KO mice, the concentration of L-NNA and Ang II were increased to 1 g/L or 2 mg·kg-1·d-1, respectively. Arterial segments were prepared from carotid arteries and aortas, and EDC was elicited by acetylcholine in the presence of Nω-nitro-L-arginine methyl ester. We showed that low concentration of acetylcholine (3-30 nM) initiated relaxation in phenylephrine-precontracted carotid arteries of both normotensive and hypertensive mice, while high concentration of acetylcholine (0.1-2 µM) induced contraction. Application of selective Orai1 inhibitors AnCoA4 (100 µM) or YM58483 (400 nM) had no effect on ACh-induced relaxation but markedly reduced acetylcholine-induced EDC. We found that EDC was increased in hypertensive mice compared with that of normotensive mice, which was associated with increased Orai1 expression in endothelial cells of hypertensive mice. Compared to TRPC5 and TRPV4, which were also involved in EDC, endothelial cell Orai1 had relatively greater contribution to EDC than either TRPC5 or TRPV4 alone. We identified COX-2, followed by PGF2α, PGD2 and PGE2 as the downstream signals of Orai1/TRPC5/TRPV4. In conclusion, Orai1 coordinates together with TRPC5 and TRPV4 in endothelial cells to regulate EDC responses. This study demonstrates a novel function of Orai1 in EDC in both normotensive and hypertensive mice, thus providing a general scheme about the control of EDC by Ca2+-permeable channels.
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Arterias Carótidas , Células Endoteliales , Endotelio Vascular , Hipertensión , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína ORAI1 , Canales Catiónicos TRPC , Animales , Proteína ORAI1/metabolismo , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Canales Catiónicos TRPC/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Acetilcolina/farmacología , Angiotensina II/farmacología , Vasoconstricción/efectos de los fármacos , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). METHODS: The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as "mean GSM-CCA value." RESULTS: In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] - 1.24[- 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] - 2.33[- 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] - 0.29 [- 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. CONCLUSIONS: The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Arterias Carótidas/efectos de los fármacos , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adulto , Anciano , Compuestos de Bencidrilo/efectos adversos , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Glucósidos/efectos adversos , Humanos , Japón , Masculino , Persona de Mediana Edad , Placa Aterosclerótica , Estudios Prospectivos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: In recent years, several trials investigated the role of anti-inflammatory agents in reducing cardiovascular events. Trehalose is a natural disaccharide able to reduce inflammation by enhancing macrophage autophagic activity. This action has been demonstrated to attenuate atherosclerotic plaque development in various pro-atherogenic animal models. However, at present, no data about the efficacy of this compound in human subjects have been published. METHODS: We performed a randomized, double-blind trial involving 15 patients with history of myocardial infarction and evidence of systemic inflammation (defined as C-reactive protein > 2 mg/L). The patients were randomly assigned, in 2:1 ratio, to receive either intravenous trehalose (15 g once weekly) or placebo for 12 weeks. The primary efficacy end-point was the change in arterial wall inflammation, assessed by quantifying 18F-FDG PET/CT uptake in carotid arteries and ascending aorta. RESULTS: The MDS TBR change of the index vessel at 3-month follow-up was not significant in treatment and placebo groups. Furthermore, we could not demonstrate any significant difference between the trehalose group and control group in changes of cIMT from baseline to 3 months in the overall population. No significant changes in echocardiographic measurement were noted after trehalose treatment. Except for the change in urea level in placebo group (31.00 ± 6.59 vs. 25.60 ± 6.402 P = 0.038) no other changes were detected after treatment. Also, there was a significant difference between changes in alanine aminotransferase (ALT) trehalose and placebo groups. CONCLUSION: This was the first study that specifically assessed the effects of intravenous trehalose on atherogenesis in human subjects. Trehalose treatment was characterized by an optimal safety profile, but no significant reduction in arterial wall inflammation could be observed. This might be a consequence of the small sample size of this trial. Larger studies are needed to better assess the efficacy of this compound in this clinical context.
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Antiinflamatorios/farmacología , Inflamación/patología , Infarto del Miocardio/patología , Trehalosa/farmacología , Aorta/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Enfermedad de la Arteria Coronaria/patología , Método Doble Ciego , Humanos , Enfermedades Vasculares/patologíaRESUMEN
OBJECTIVE: Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H2S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H2S. Here, it was hypothesised that zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. METHODS: Spontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. RESULTS: Compared with control animals (intima/media thickness 2.3 ± 0.33 µm), enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7 ± 0.35 µm; p = .037), while zofenopril abrogated IH (0.4 ± 0.16 µm; p < .002 vs. control and p > .99 vs. sham operated Cx40-/- mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 µm in control vs. 1.140 ± 0.27 µm; p > .99), while zofenopril also abrogated IH (0.1623 ± 0.07 µm; p < .008 vs. control and p > .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments ex vivo. The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. CONCLUSION: Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.
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Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Captopril/análogos & derivados , Estenosis Carotídea/tratamiento farmacológico , Hipertensión/complicaciones , Túnica Íntima/patología , Animales , Presión Sanguínea/efectos de los fármacos , Captopril/administración & dosificación , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Estenosis Carotídea/etiología , Estenosis Carotídea/patología , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Sulfuro de Hidrógeno/metabolismo , Hiperplasia/tratamiento farmacológico , Hiperplasia/patología , Hipertensión/tratamiento farmacológico , Masculino , Ratones , Miocitos del Músculo Liso , Técnicas de Cultivo de Órganos , Cultivo Primario de Células , Túnica Íntima/efectos de los fármacos , Venas/efectos de los fármacos , Venas/patologíaRESUMEN
Vascular restenosis remains a major problem in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Neointimal hyperplasia, defined by post-procedure proliferation and migration of vascular smooth muscle cells (VSMCs) is a key underlying pathology. Here we investigated the role of Interleukin 11 (IL-11) in a mouse model of injury-related plaque development. Apoe-/- mice were fed a hyperlipidaemic diet and subjected to carotid wire injury of the right carotid. Mice were injected with an anti-IL11 antibody (X203), IgG control antibody or buffer. We performed ultrasound analysis to assess vessel wall thickness and blood velocity. Using histology and immunofluorescence approaches, we determined the effects of IL-11 inhibition on VSMC and macrophages phenotypes and fibrosis. Treatment of mice with carotid wire injury using X203 significantly reduced post-endothelial injury vessel wall thickness, and injury-related plaque, when compared to control. Immunofluorescence staining of the injury-related plaque showed that X203 treatment did not reduce macrophage numbers, but reduced the number of VSMCs and lowered matrix metalloproteinase 2 (MMP2) levels and collagen content in comparison to control. X203 treatment was associated with a significant increase in smooth muscle protein 22α (SM22α) positive cells in injury-related plaque compared to control, suggesting preservation of the contractile VSMC phenotype. Interestingly, X203 also reduced the collagen content of uninjured carotid arteries as compared to IgG, showing an additional effect on hyperlipidemia-induced arterial remodeling in the absence of mechanical injury. Therapeutic inhibition of IL-11 reduced vessel wall thickness, attenuated neointimal hyperplasia, and has favorable effects on vascular remodeling following wire-induced endothelial injury. This suggests IL-11 inhibition as a potential novel therapeutic approach to reduce arterial stenosis following revascularization in CAD and PAD patients.
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Anticuerpos Neutralizantes/farmacología , Arterias Carótidas/efectos de los fármacos , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Hiperplasia/tratamiento farmacológico , Interleucina-11/metabolismo , Animales , Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Hiperplasia/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Neointima/tratamiento farmacológico , Neointima/metabolismo , Remodelación Vascular/efectos de los fármacosRESUMEN
AIMS: Clinically, Cerebralcare Granule® (CG) has been widely utilized to treat various types of headache, chronic cerebral insufficiency and other diseases, and the effect is significant. Clinical studies have shown that CG can significantly relieve vascular dementia (VaD), however, the molecular mechanisms haven't been established. To clear the therapeutic mechanisms of CG against VaD, a hypothesis was proposed that CG could treat neurovascular injury by inhibiting the production of lipocalin-2 (LCN 2). MAIN METHODS: 90 dementia rats were selected by water maze test and randomly divided into 6 groups, including nimodipine (NM), CG L (low dose) (0.314 g kg-1), CG H (high dose) (0.628 g kg-1), and combined group (CG + NM). And in vitro neuronal cell OGD modeling to evaluate the effect of CG on JAK2/STAT3. KEY FINDINGS: CG could significantly shorten the escape latency of two-vessel occlusion (2-VO) rats, increase their exploratory behavior, alleviate the symptoms of VaD and improve the ultrastructural pathological damage of neurovascular unit and accelerate the recovery of cerebral blood perfusion. CG combined with NM is better than NM alone. It was further showed that CG could inhibit the pathogenicity of LCN 2 through JAK2/STAT3 pathway and suppress the production of inflammatory cytokines. It plays a role in the protection of cerebral microvasculature and BBB in 2-VO rats. SIGNIFICANCE: Taken together, there data has supported notion that CG can protect the integrity of cerebral blood vessels and BBB and improve cognitive impairment through mainly inhibiting LCN 2, which provides scientific evidence for clinical application.
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Disfunción Cognitiva/tratamiento farmacológico , Medicamentos Herbarios Chinos/metabolismo , Lipocalina 2/metabolismo , Animales , Arterias Carótidas/efectos de los fármacos , China , Disfunción Cognitiva/fisiopatología , Demencia Vascular/prevención & control , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Lipocalina 2/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nimodipina/metabolismo , Nimodipina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
ABSTRACT: This retrospective study appraised the preventive effect of statin after carotid artery stenting (CAS).Records were extracted for 100 patients with CAS surgery indicator, aged between 20 and 75âyears old, and treated for statin. The cohort study included treatment group (statin and routine treatment) and control group (routine treatment), each group 50 patients. Outcomes consisted of degree of nerve defect (as measured by National Institute of Health Stroke Scale), lipid profiles (mg/dL), and CAS complications within 30âdays after surgery.After treatment, there were no significant differences in National Institute of Health Stroke Scale, lipid profiles, and mortality rate between 2 groups. However, significant differences in total cholesterol (mg/dL, Pâ=â.03), low-density lipoprotein (mg/dL, Pâ=â.01), transient ischemic attack (Pâ=â.03), ischemic stroke (Pâ=â.04), and cardiac complications (Pâ=â.03) were identified within 30âdays after CAS between 2 groups.The results of this study showed that prior statin treatment may be effective for the prevention of CAS complications.
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Arterias Carótidas/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/normas , Stents/normas , Anciano , Arterias Carótidas/fisiopatología , China/epidemiología , Estudios de Cohortes , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Estadísticas no Paramétricas , Stents/estadística & datos numéricos , Resultado del TratamientoRESUMEN
Severe burns result in cardiovascular dysfunction, but responses in the peripheral vasculature are unclear. We hypothesize that severe burns disturb arterial contractility through acute changes in adrenergic and cholinergic receptor function. To address this, we investigated the changes in carotid artery contractility and relaxation following a severe burn. Thirty-four adult Sprague-Dawley male rats received a 40% total body surface area (TBSA) scald burn and fluid resuscitation using the Parkland formula. Control animals received sham burn procedure. Animals were serially euthanized between 6 h and 14 days after burn and endothelium-intact common carotid arteries were used for ex vivo force/relaxation measurements. At 6 h after burn, carotid arteries from burned animals demonstrated a > 50% decrease in cumulative dose-responses to norepinephrine (p < 0.05) and to 10-7 M angiotensin II (p < 0.05). Notably, pre-constricted carotid arteries also demonstrated reduced relaxation responses to acetylcholine (p < 0.05) 6 h after burn, but not to sodium nitroprusside. Histologic examination of cross-sectional planes revealed significant increases in carotid artery wall thickness in burned rats at 6 h versus 3 days, with increased collagen expression in tunica media at 3 days (p < 0.05). Carotid artery dysfunction occurs within 6 h after severe burn, demonstrating decreased sensitivity to adrenergic- and angiotensin II-induced vasoconstriction and acetylcholine-induced relaxation.
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Quemaduras/fisiopatología , Arterias Carótidas/fisiopatología , Músculo Liso Vascular/fisiopatología , Vasoconstricción , Animales , Biomarcadores , Quemaduras/diagnóstico , Quemaduras/etiología , Quemaduras/metabolismo , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Cloruro de Potasio/farmacología , Ratas , Vasoconstricción/efectos de los fármacosRESUMEN
Formaldehyde (FA) is a ubiquitous organic preservative used in several industries and represents an occupational health hazard. Short-term exposure to FA can increase oxidative stress and cause a decrease in conduit vessel function. These decrements in vascular function may extend to the arterial architecture, predisposing individuals to increased risk of cardiovascular disease. The purpose of this study was to investigate the impact of an acute 90-minute FA exposure period (259 ± 95 ppb) on indices of arterial architecture. Arterial stiffness and carotid distensibility as determined by central pressures, augmentation index (AIx), and carotid-femoral pulse wave velocity (cfPWV) (n=13F, 24 ± 1 year) as well as carotid stiffness and intima media thickness (IMT) (n = 9F, 23 ± 1 year) were assessed prior to (Pre-FA) and immediately following (Post-FA) exposure to FA in human cadaver dissection laboratories. Central pressures and cfPWV (Pre-FA: 5.2 ± 0.8 m.s-1, Post-FA: 5.2 ± 1.1 m s-1) were unchanged by acute FA exposure (p > 0.05). Carotid stiffness parameters and distension were unchanged by acute FA exposure (p > 0.05), although distensibility (Pre-FA: 33.9 ± 10.5[10-3*kPa-1], Post-FA: 25.9 ± 5.5[10-3*kPa-1], p < 0.05), and IMT (Pre-FA: 0.42 ± 0.05 mm, Post-FA: 0.51 ± 0.11 mm, p < 0.05) decreased and increased, respectively. Individual Pre- to Post-FA changes in these markers of arterial architecture did not correlate with levels of FA exposure ([FA]: 20-473 ppb) (p > 0.05). Our group previously found vascular function decrements following acute FA exposure in human cadaver laboratories; here we found that carotid distensibility and intima media thickness are altered following FA exposure.
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Arterias Carótidas/efectos de los fármacos , Formaldehído/efectos adversos , Exposición Profesional/efectos adversos , Rigidez Vascular/efectos de los fármacos , Adolescente , Cadáver , Grosor Intima-Media Carotídeo , Femenino , Formaldehído/farmacología , Humanos , Hipersensibilidad RespiratoriaRESUMEN
Endothelial dysfunction is the pathological basis of atherosclerosis. Incomplete understanding of endothelial dysfunction etiology has impeded drug development for this devastating disease despite the currently available therapies. Floralozone, an aroma flavor, specifically exists in rabbit ear grass. Recently, floralozone has been demonstrated to inhibit atherosclerosis, but the underlying mechanisms are undefined. The present study was undertaken to explore whether floralozone pharmacologically targets endothelial dysfunction and therefore exerts therapeutic effects on atherosclerosis. The Na+/H+ exchanger 1 (NHE1), a channel protein, plays a vital role in atherosclerosis. Whether NHE1 is involved in the therapeutic effects of floralozone on endothelial dysfunction has yet to be further answered. By performing oil red staining and hematoxylin-eosin staining, vascular functional study, and oxidative stress monitoring, we found that floralozone not only reduced the size of carotid atherosclerotic plaque but also prevented endothelial dysfunction in atherosclerotic rats. NHE1 expression was upregulated in the inner membrane of carotid arteries and H2O2-induced primary rat aortic endothelial cells. Inspiringly, floralozone prevented the upregulation of NHE1 in vivo and in vitro. Notably, the administration of NHE1 activator LiCl significantly weakened the protective effect of floralozone on endothelial dysfunction in vivo and in vitro. Our study demonstrated that floralozone exerted its protective effect on endothelial dysfunction in atherosclerosis by ameliorating NHE1. NHE1 maybe a drug target for the treatment of atherosclerosis, and floralozone may be an effective drug to meet the urgent needs of atherosclerosis patients by dampening NHE1.
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Aterosclerosis , Endotelio Vascular , Extractos Vegetales , Sustancias Protectoras , Intercambiador 1 de Sodio-Hidrógeno , Animales , Masculino , Aorta/citología , Aorta/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/prevención & control , Arterias Carótidas/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Placa Aterosclerótica/prevención & control , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Ratas Sprague-Dawley , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 1 de Sodio-Hidrógeno/metabolismoRESUMEN
During operations, surgical mesh is commonly fixed on tissues through fasteners such as sutures and staples. Attributes of surgical mesh include biocompatibility, flexibility, strength, and permeability, but sutures and staples may cause stress concentration and tissue damage. Here, we show that the functions of surgical mesh can be significantly broadened by developing a family of materials called hydrogel-mesh composites (HMCs). The HMCs retain all the attributes of surgical mesh and add one more: adhesion to tissues. We fabricate an HMC by soaking a surgical mesh with a precursor, and upon cure, the precursor forms a polymer network of a hydrogel, in macrotopological entanglement with the fibers of the surgical mesh. In a surgery, the HMC is pressed onto a tissue, and the polymers in the hydrogel form covalent bonds with the tissue. To demonstrate the concept, we use a poly(N-isopropylacrylamide) (PNIPAAm)/chitosan hydrogel and a polyethylene terephthalate (PET) surgical mesh. In the presence a bioconjugation agent, the chitosan and the tissue form covalent bonds, and the adhesion energy reaches above 100 Jâ m-2 At body temperature, PNIPAAm becomes hydrophobic, so that the hydrogel does not swell and the adhesion is stable. Compared with sutured surgical mesh, the HMC distributes force over a large area. In vitro experiments are conducted to study the application of HMCs to wound closure, especially on tissues under high mechanical stress. The performance of HMCs on dynamic living tissues is further investigated in the surgery of a sheep.
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Hidrogeles/farmacología , Mallas Quirúrgicas , Cicatrización de Heridas , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Femenino , Hígado/efectos de los fármacos , Hígado/patología , Ovinos , Adhesivos Tisulares/farmacología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 mo) and old (27 mo) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young and 7 old) or apigenin (0.5 mg/mL in vehicle; 10 young and 9 old) for 6 wk. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old versus young (70% ± 9% vs. 92% ± 1%, P < 0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of Tempol (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434 ± 9 vs. 346 ± 5 cm/s, P < 0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end products (AGEs), and proinflammatory cytokine abundance. In old mice, apigenin restored EDD (96% ± 2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress, and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373 ± 5 cm/s) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.NEW & NOTEWORTHY Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.
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Envejecimiento/metabolismo , Endotelio Vascular/efectos de los fármacos , Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Espirostanos/farmacología , Rigidez Vascular/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Endotelio Vascular/metabolismo , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismoRESUMEN
It has been demonstrated that trimethylamine N-oxide (TMAO) serves as a driver of atherosclerosis, suggesting that reduction of TMAO level might be a potent method to prevent the progression of atherosclerosis. Herein, we explored the role of TMAO in the stability of carotid atherosclerotic plaques and disclosed the underlying mechanisms. The unstable carotid artery plaque models were established in C57/BL6 mice. L-carnitine (LCA) and methimazole (MMI) administration were applied to increase and reduce TMAO levels. Hematoxylin and eosin (H&E) staining, Sirius red, Perl's staining, Masson trichrome staining and immunohistochemical staining with CD68 staining were used for histopathology analysis of the carotid artery plaque. M1 and M2 macrophagocyte markers were assessed by RT-PCR to determine the polarization of RAW264.7 cells. MMI administration for 2 weeks significantly decreased the plaque area, increased the thickness of the fibrous cap and reduced the size of the necrotic lipid cores, whereas 5-week of administration of MMI induced intraplate hemorrhage. LCA treatment further deteriorated the carotid atherosclerotic plaque but with no significant difference. In mechanism, we found that TMAO treatment impaired the M2 polarization and efferocytosis of RAW264.7 cells with no obvious effect on the M1 polarization. In conclusion, the present study demonstrated that TMAO reduction enhanced the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.