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1.
Circ Res ; 128(5): e84-e101, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33508947

RESUMO

RATIONALE: Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure, and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP-associated variants and target genes. OBJECTIVE: To establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci. METHODS AND RESULTS: We mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 nonpathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing. Open chromatin peaks were globally similar between pathogenic and nonpathogenic valves. Compared with the heart tissue and cardiac fibroblasts, we found that MV-specific assay for transposase-accessible chromatin with high-throughput sequencing peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motifs in MV-specific open chromatin peaks was for the nuclear factor of activated T cells family of TFs (transcription factors) involved in valve endocardial and interstitial cell formation. We also found that MVP-associated variants were significantly enriched (P<0.05) in mitral valve open chromatin peaks. Integration of the assay for transposase-accessible chromatin with high-throughput sequencing data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. Circular chromatin conformation capture followed by high-throughput sequencing experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on chromosome 2. CONCLUSIONS: Here, we describe unprecedented genome-wide open chromatin profiles from human pathogenic and nonpathogenic MVs and report specific gene regulation profiles, compared with the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Cromatina/genética , Prolapso da Valva Mitral/genética , Valva Mitral/metabolismo , Polimorfismo de Nucleotídeo Único , Células Cultivadas , Cromatina/metabolismo , Fibroblastos/metabolismo , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Prolapso da Valva Mitral/metabolismo , Telomerase/genética , Tensinas/genética , Transcriptoma
2.
Molecules ; 27(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35744803

RESUMO

Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in cancer treatment, newly approved oncology drugs are associated with increased toxicity risk. These toxicities may be mitigated by pharmacokinetic optimization and reductions in off-target interactions. As such, there is a need for early-stage implementation of pharmacokinetic (PK) prediction tools. Several PK prediction platforms exist, including pkCSM, SuperCypsPred, Pred-hERG, Similarity Ensemble Approach (SEA), and SwissADME. These tools can be used in screening hits, allowing for the selection of compounds were reduced toxicity and/or risk of attrition. In this short commentary, we used PK prediction tools in the optimization of mitogen activated extracellular signal-related kinase kinase 1 (MEK1) inhibitors. In doing so, we identified MEK1 inhibitors with retained activity and optimized predictive PK properties, devoid of hERG inhibition. These data support the use of publicly available PK prediction platforms in early-stage drug discovery to design safer drugs.


Assuntos
Antineoplásicos , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
3.
Dev Dyn ; 250(10): 1432-1449, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33811421

RESUMO

BACKGROUND: Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood. RESULTS: A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and ß-catenin. Co-expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of ß-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of ß-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased ß-catenin activities. The ß-catenin target gene, MMP2 was up-regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype. CONCLUSION: Dzip1 functions to restrain ß-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear ß-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/metabolismo , Valvas Cardíacas/embriologia , Prolapso da Valva Mitral/metabolismo , Organogênese/fisiologia , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Células HEK293 , Valvas Cardíacas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Prolapso da Valva Mitral/genética , Fenótipo , Transdução de Sinais/fisiologia
4.
Dev Biol ; 463(1): 26-38, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32151560

RESUMO

Non-syndromic mitral valve prolapse (MVP) is the most common heart valve disease affecting 2.4% of the population. Recent studies have identified genetic defects in primary cilia as causative to MVP, although the mechanism of their action is currently unknown. Using a series of gene inactivation approaches, we define a paracrine mechanism by which endocardially-expressed Desert Hedgehog (DHH) activates primary cilia signaling on neighboring valve interstitial cells. High-resolution imaging and functional assays show that DHH de-represses smoothened at the primary cilia, resulting in kinase activation of RAC1 through the RAC1-GEF, TIAM1. Activation of this non-canonical hedgehog pathway stimulates α-smooth actin organization and ECM remodeling. Genetic or pharmacological perturbation of this pathway results in enlarged valves that progress to a myxomatous phenotype, similar to valves seen in MVP patients. These data identify a potential molecular origin for MVP as well as establish a paracrine DHH-primary cilium cross-talk mechanism that is likely applicable across developmental tissue types.


Assuntos
Cílios/metabolismo , Proteínas Hedgehog/metabolismo , Valva Mitral/embriologia , Actinas/metabolismo , Animais , Matriz Extracelular/metabolismo , Doenças das Valvas Cardíacas , Proteínas Hedgehog/fisiologia , Camundongos , Prolapso da Valva Mitral/genética , Prolapso da Valva Mitral/metabolismo , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Miócitos de Músculo Liso/metabolismo , Neuropeptídeos/metabolismo , Fenótipo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
5.
J Biol Chem ; 294(17): 6710-6718, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30824539

RESUMO

The exocyst is a highly conserved protein complex found in most eukaryotic cells and is associated with many functions, including protein translocation in the endoplasmic reticulum, vesicular basolateral targeting, and ciliogenesis in the kidney. To investigate the exocyst functions, here we exchanged proline for alanine in the highly conserved VXPX ciliary targeting motif of EXOC5 (exocyst complex component 5), a central exocyst gene/protein, and generated stable EXOC5 ciliary targeting sequence-mutated (EXOC5CTS-m) Madin-Darby canine kidney (MDCK) cells. The EXOC5CTS-m protein was stable and could bind other members of the exocyst complex. Culturing stable control, EXOC5-overexpressing (OE), Exoc5-knockdown (KD), and EXOC5CTS-m MDCK cells on Transwell filters, we found that primary ciliogenesis is increased in EXOC5 OE cells and inhibited in Exoc5-KD and EXOC5CTS-m cells. Growing cells in collagen gels until the cyst stage, we noted that EXOC5-OE cells form mature cysts with single lumens more rapidly than control cysts, whereas Exoc5-KD and EXOC5CTS-m MDCK cells failed to form mature cysts. Adding hepatocyte growth factor to induce tubulogenesis, we observed that EXOC5-OE cell cysts form tubules more efficiently than control MDCK cell cysts, EXOC5CTS-m MDCK cell cysts form significantly fewer tubules than control cell cysts, and Exoc5-KD cysts did not undergo tubulogenesis. Finally, we show that EXOC5 mRNA almost completely rescues the ciliary phenotypes in exoc5-mutant zebrafish, unlike the EXOC5CTS-m mRNA, which could not efficiently rescue the phenotypes. Taken together, these results indicate that the exocyst, acting through the primary cilium, is necessary for renal ciliogenesis, cystogenesis, and tubulogenesis.


Assuntos
Cílios/fisiologia , Cistos/patologia , Túbulos Renais/crescimento & desenvolvimento , Rim/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , DNA Complementar/genética , Cães , Técnicas de Silenciamento de Genes , Humanos , Nefropatias/patologia , Células Madin Darby de Rim Canino , Mutagênese Sítio-Dirigida , Ligação Proteica , Transporte Proteico , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/genética , Peixe-Zebra
6.
Circulation ; 140(16): 1331-1341, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31387361

RESUMO

BACKGROUND: Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities. METHODS: We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography. RESULTS: Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models. CONCLUSIONS: These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/anormalidades , Cílios/fisiologia , Cardiopatias Congênitas/patologia , Doenças das Valvas Cardíacas/patologia , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Doença da Válvula Aórtica Bicúspide , Estudos de Casos e Controles , Cílios/patologia , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias Congênitas/genética , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
7.
J Biol Chem ; 292(36): 14814-14826, 2017 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-28729419

RESUMO

We previously have shown that the highly conserved eight-protein exocyst trafficking complex is required for ciliogenesis in kidney tubule cells. We hypothesized here that ciliogenic programs are conserved across organs and species. To determine whether renal primary ciliogenic programs are conserved in the eye, and to characterize the function and mechanisms by which the exocyst regulates eye development in zebrafish, we focused on exoc5, a central component of the exocyst complex, by analyzing both exoc5 zebrafish mutants, and photoreceptor-specific Exoc5 knock-out mice. Two separate exoc5 mutant zebrafish lines phenocopied exoc5 morphants and, strikingly, exhibited a virtual absence of photoreceptors, along with abnormal retinal development and cell death. Because the zebrafish mutant was a global knockout, we also observed defects in several ciliated organs, including the brain (hydrocephalus), heart (cardiac edema), and kidney (disordered and shorter cilia). exoc5 knockout increased phosphorylation of the regulatory protein Mob1, consistent with Hippo pathway activation. exoc5 mutant zebrafish rescue with human EXOC5 mRNA completely reversed the mutant phenotype. We accomplished photoreceptor-specific knockout of Exoc5 with our Exoc5 fl/fl mouse line crossed with a rhodopsin-Cre driver line. In Exoc5 photoreceptor-specific knock-out mice, the photoreceptor outer segment structure was severely impaired at 4 weeks of age, although a full-field electroretinogram indicated a visual response was still present. However, by 6 weeks, visual responses were eliminated. In summary, we show that ciliogenesis programs are conserved in the kidneys and eyes of zebrafish and mice and that the exocyst is necessary for photoreceptor ciliogenesis and retinal development, most likely by trafficking cilia and outer-segment proteins.


Assuntos
Cílios/metabolismo , Exocitose , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Células Fotorreceptoras de Vertebrados/patologia , Retina/patologia , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/metabolismo , Peixe-Zebra
8.
Dev Dyn ; 246(8): 625-634, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28556366

RESUMO

BACKGROUND: Bicuspid aortic valve (BAV) disease is the most common congenital heart defect, affecting 0.5-1.2% of the population and causing significant morbidity and mortality. Only a few genes have been identified in pedigrees, and no single gene model explains BAV inheritance, thus supporting a complex genetic network of interacting genes. However, patients with rare syndromic diseases that stem from alterations in the structure and function of primary cilia ("ciliopathies") exhibit BAV as a frequent cardiovascular finding, suggesting primary cilia may factor broadly in disease etiology. RESULTS: Our data are the first to demonstrate that primary cilia are expressed on aortic valve mesenchymal cells during embryonic development and are lost as these cells differentiate into collagen-secreting fibroblastic-like cells. The function of primary cilia was tested by genetically ablating the critical ciliogenic gene Ift88. Loss of Ift88 resulted in abrogation of primary cilia and increased fibrogenic extracellular matrix (ECM) production. Consequentially, stratification of ECM boundaries normally present in the aortic valve were lost and a highly penetrant BAV phenotype was evident at birth. CONCLUSIONS: Our data support cilia as a novel cellular mechanism for restraining ECM production during aortic valve development and broadly implicate these structures in the etiology of BAV disease in humans. Developmental Dynamics 246:625-634, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Valva Aórtica/anormalidades , Valva Aórtica/metabolismo , Cílios/metabolismo , Cílios/fisiologia , Doenças das Valvas Cardíacas/metabolismo , Animais , Valva Aórtica/crescimento & desenvolvimento , Doença da Válvula Aórtica Bicúspide , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Matriz Extracelular/metabolismo , Feminino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
9.
Zhonghua Yi Xue Za Zhi ; 95(8): 601-5, 2015 Mar 03.
Artigo em Chinês | MEDLINE | ID: mdl-25917037

RESUMO

OBJECTIVE: To establish a murine model of hindlimb ischemia and denervation and evaluate the effects of neural factors on angiogenesis and skeletal muscle fiber remodeling. METHODS: A total of 54 mice were randomly allocated into three groups of control (n = 6), hindlimb ischemia (n = 24), hindlimb ischemia and denervation (n = 24). The model of hindlimb ischemia was established by ligating femoral artery. And the model of hindlimb ischemia and denervation was established by transecting sciatic nerve on the basis of hindlimb ischemia modeling. Gastrocnemius of ischemic hindlimbs were harvested under the condition of peritoneal cavity anesthesia at Days 7, 14, 21 and 28 postoperation. And then the mice were sacrificed. The gastrocnemius of three groups were tested by hematoxylin-eosin staining, CD31 and PCNA immunohistochemical staining and myosin ATPase staining. The protein expressions of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) were detected by enzyme-linked immunosorbent assay. RESULTS: At Day 7 postoperation, hindlimbs of two intervention groups showed ischemic manifestations as compared with controls. And semiquantitative assessment of ischemic damage showed the proportion level I-IV of hindlimb ischemia and denervation group was significantly higher than that of hindlimb ischemia group (33.4% vs. 16.6%, χ(2) = 7.94, P = 0.047). At Day 28 postoperation, the values of endothelial cell proliferation index [(2.4 ± 0.4)% vs. (5.7 ± 1.0)%, P = 0.000], capillary density [(0.44 ± 0.05) vs. (0.61 ± 0.07), P = 0.000], NGF protein expression [(6.71 ± 0.94) vs. (8.36 ± 0.77) pg/ml, P = 0.008] and VEGF protein expression [(11.32 ± 1.56) vs. (15.13 ± 2.93) pg/ml, P = 0.018] of hindlimb ischemia and denervation group significantly decreased as compared with hindlimb ischemia group. At Day 28 postoperation, the proportion of type II muscle fiber in gastrocnemius was significantly higher than that of hindlimb ischemia group [(84.9 ± 3.8)% vs. (78.8 ± 1.8)%, P = 0.008]. CONCLUSION: Neural factors play important roles in promoting angiogenesis and maintaining muscle fiber types in ischemic limbs. But its molecular regulatory mechanism requires further studies.


Assuntos
Membro Posterior , Isquemia , Músculo Esquelético , Animais , Capilares , Denervação , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Camundongos , Fibras Musculares Esqueléticas , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular
10.
Ann Vasc Surg ; 28(7): 1791.e9-1791.e11, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24632320

RESUMO

Cavernous transformation of the portal vein (CTPV) is a mass-like network of collateral veins around the portal vein as the sequel to extrahepatic portal vein obstruction. The common clinical manifestations include esophageal varices, splenomegaly, and hypersplenism. The patient may present with recurrent hematemesis and tarry stool. We report a woman who presented with CTPV, which was managed with an unconventional interventional method to recanalize the superior mesenteric vein and main portal vein.


Assuntos
Hipertensão Portal/patologia , Hipertensão Portal/cirurgia , Veia Porta/patologia , Adulto , Angiografia , Circulação Colateral , Feminino , Humanos , Transplante de Fígado , Tomografia Computadorizada por Raios X
11.
Zhonghua Yi Xue Za Zhi ; 94(11): 828-31, 2014 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-24854749

RESUMO

OBJECTIVE: To analyze the diagnosis, treatment and prognosis of the malignant carotid body tumor. METHODS: The data of pathology, diagnosis, therapy and follow-up of seven patients with malignant carotid body tumor in Peking Union Medical College Hospital from Dec 1949 to Dec 2012 were analyzed retrospectively. RESULTS: 2 cases without the tumor resection. 5 cases were treated with surgical methods, 4 cases with tumor resection and external carotid artery ligation, 1 case with tumor resection and reconstruction of internal carotid artery with saphenous vein. Cranial nerve palsy occurred in 5 cases, of which 3 occurred hypoglossal nerve damage, 2 cases occurred vagus damage, 1 case with hypoglossal, vagus and sympathetic nerve damage. Follow-up was from 2 to 12 years. local tumor recurrence happened in 2-year postoperation and got remote bone and pancreas metastasis in 5-year postoperation in one case, and finally died in 7-year postoperation. 1 case had the internal carotid artery restenosis severely in 1-year postoperation, then performed the stent treatment. 2 cases without operation were still alive. Interestingly, the tumor after radiotherapy was steady in one case. The other received the tumor resection because of the severe syndrome after 8 years. CONCLUSION: the diagnosis of malignant carotid body tumor should base on occurring extensive invasion of adjacent organs, metastasis and pathology. Early stage surgical excision can reduce the recurrence and complication. Radiotherapy can effectively control local size and distant metastasis.


Assuntos
Tumor do Corpo Carotídeo/diagnóstico , Tumor do Corpo Carotídeo/terapia , Adulto , Tumor do Corpo Carotídeo/cirurgia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
12.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 36(2): 131-4, 2014 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-24791790

RESUMO

OBJECTIVE: To analyze the effectiveness and costs of the eversion carotid endarterectomy (eCEA) and the carotid endarterectomy with patch angioplasty (pCEA) in treating carotid artery stenosis. METHODS: Patients with carotid artery stenosis who underwent the carotid endarterectomy in the vascular surgery department of Peking Union Medical College Hospital from October 2009 to October 2012 were enrolled in this study. According to the two different surgical procedures, the patients were divided into eCEA group and pCEA group. RESULTS: The two groups were not significantly different in terms of gender ,age ,risk factors, stenosis degree of carotid artery, and the ratio of bilateral lesions (all P>0.05).The ratio of shunt and antibiotics application, operative time, hospitalization cost, and length of hospital stay in the eCEA group were significantly lower than those in pCEA group (P<0.05).The therapeutic effectiveness, complications, surgery-related death, restenosis, and ipsilateral stroke were not significantly different between these two groups (P>0.05). CONCLUSION: Both surgical procedures are safe and effective in treating the carotid artery stenosis;however, eCEA has lower cost when compared with pCEA and therefore can be used as the first choice.


Assuntos
Artéria Carótida Interna/cirurgia , Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Zhonghua Yi Xue Za Zhi ; 93(27): 2135-8, 2013 Jul 16.
Artigo em Chinês | MEDLINE | ID: mdl-24284244

RESUMO

OBJECTIVE: To analyze the efficacy and safety of eversion carotid endarterectomy (eCEA) and carotid endarterectomy with patch angioplasty (pCEA) in the treatment of carotid artery stenosis. METHODS: The clinical data were collected and analyzed for the patients with carotid artery stenosis undergoing carotid endarterectomy at Department of Vascular Surgery, Peking Union Medical College Hospital from October 2009 to October 2012. According to two different surgical procedures, they were divided into 2 groups of eCEA and pCEA. RESULTS: A total of 248 patients received a follow-up. Among 274 cases of endarterectomy, 101 cases of eCEA and 173 cases of pCEA were performed. No significant difference (P > 0.05) existed between two groups in gender, age, risk factors, stenotic degree of carotid artery or ratio of bilateral lesions. The ratio of shunt (15.8%) and antibiotics (26.7%) application, the duration of operation (88 ± 20) min, intraoperative blood loss (45 ± 16) ml and the length of stay (16 ± 4) days in the group eCEA were significantly lower than those of group pCEA (P < 0.05). There was no significant difference (P > 0.05) between two groups in the ratio of complications, surgery-related mortality, restenosis and ipsilateral stroke. CONCLUSION: Both surgical procedures are both safe and effective in the treatment of carotid artery stenosis. However eCEA offers potential advantages. The choice of a particular surgical procedure depends on the surgeon experience and specific circumstances of carotid artery lesions.


Assuntos
Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Foods ; 12(18)2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37761153

RESUMO

This study synthesized the NaGdF4@NaGdF4: Yb, Tm@NaGdF4: Yb, Nd upconversion nanoparticles (UCNPs), combined with another three-layer structure NaYF4@NaYF4: Yb, Er@NaYF4 UCNPs, with a core-shell-shell structure, effectively suppressing fluorescence quenching and significantly improving upconversion luminescence efficiency. Two types of modified UCNPs were coupled with antibodies against fenpropathrin and procymidone to form signal probes, and magnetic nanoparticles were coupled with antigens of fenpropathrin and procymidone to form capture probes. A rapid and sensitive fluorescence immunoassay for the simultaneous detection of fenpropathrin and procymidone was established based on the principle of specific binding of antigen and antibody and magnetic separation technology. Under the optimal competitive reaction conditions, different concentrations of fenpropathrin and procymidone standards were added to collect the capture probe-signal probe complex. The fluorescence values at 542 nm and 802 nm were measured using 980 nm excitation luminescence. The results showed that the detection limits of fenpropathrin and procymidone were 0.114 µg/kg and 0.082 µg/kg, respectively, with sensitivities of 8.15 µg/kg and 7.98 µg/kg, and they were applied to the detection of fenpropathrin and procymidone in tomatoes, cucumbers, and cabbage. The average recovery rates were 86.5~100.2% and 85.61~102.43%, respectively, with coefficients of variation less than 10%. The results showed good consistency with the detection results of high-performance liquid chromatography, proving that this method has good accuracy and is suitable for the rapid detection of fenpropathrin and procymidone in food.

15.
J Cardiovasc Dev Dis ; 9(2)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35200715

RESUMO

Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.

16.
JACC CardioOncol ; 4(4): 535-548, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36444237

RESUMO

Background: Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)-mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized. Objectives: The aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function. Methods: Mice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery. Results: Long-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment. Conclusions: These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.

17.
J Cardiovasc Dev Dis ; 8(3)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805717

RESUMO

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

18.
J Am Heart Assoc ; 10(24): e022332, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34873924

RESUMO

Background Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1S14R/+). Tension-dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension-dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve-induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.


Assuntos
Cardiomiopatias , Prolapso da Valva Mitral , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Fibrose , Humanos , Camundongos , Prolapso da Valva Mitral/complicações
19.
J Cardiovasc Dev Dis ; 7(3)2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32824435

RESUMO

ß-catenin has been widely studied in many animal and organ systems across evolution, and gain or loss of function has been linked to a number of human diseases. Yet fundamental knowledge regarding its protein expression and localization remains poorly described. Thus, we sought to define whether there was a temporal and cell-specific regulation of ß-catenin activities that correlate with distinct cardiac morphological events. Our findings indicate that activated nuclear ß-catenin is primarily evident early in gestation. As development proceeds, nuclear ß-catenin is down-regulated and becomes restricted to the membrane in a subset of cardiac progenitor cells. After birth, little ß-catenin is detected in the heart. The co-expression of ß-catenin with its main transcriptional co-factor, Lef1, revealed that Lef1 and ß-catenin expression domains do not extensively overlap in the cardiac valves. These data indicate mutually exclusive roles for Lef1 and ß-catenin in most cardiac cell types during development. Additionally, these data indicate diverse functions for ß-catenin within the nucleus and membrane depending on cell type and gestational timing. Cardiovascular studies should take into careful consideration both nuclear and membrane ß-catenin functions and their potential contributions to cardiac development and disease.

20.
Anat Rec (Hoboken) ; 302(1): 117-124, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288957

RESUMO

Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that Filamin-A is required for R-Ras expression and activation of the Ras-Mek-Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for ß1-integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a ß1-integrin mechanism. As a consequence, loss of Filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117-124, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Matriz Extracelular/metabolismo , Filaminas/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Valva Mitral/metabolismo , Organogênese , Proteína Smad3/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Valva Mitral/citologia , Fenótipo
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