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1.
Genes (Basel) ; 12(6)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205376

RESUMO

Primary prevention is crucial for coronary heart disease (CAD) and the identification of new reliable biomarkers might help risk stratification or predict adverse coronary events. Alternative splicing (AS) is a less investigated genetic factors implicated in CAD etiology. We performed an RNA-seq study on PBMCs from CAD patients and control subjects (CTR) and observed 113 differentially regulated AS events (24 up and 89 downregulated) in 86 genes. The RECK (Reversion-inducing-cysteine-rich protein with Kazal motifs) gene was further analyzed in a larger case study (24 CTR subjects, 72 CAD and 32 AMI patients) for its Splicing-Index FC (FC = -2.64; p = 0.0217), the AS event involving an exon (exon 18), and its role in vascular inflammation and remodeling. We observed a significant downregulation of Long RECK splice variant (containing exon 18) in PBMCs of AMI compared to CTR subjects (FC = -3.3; p < 0.005). Interestingly, the Short RECK splice variant (lacking exon 18) was under-expressed in AMI compared to both CTR (FC = -4.5; p < 0.0001) and CAD patients (FC = -4.2; p < 0.0001). A ROC curve, constructed combining Long and Short RECK expression data, shows an AUC = 0.81 (p < 0.001) to distinguish AMI from stable CAD patients. A significant negative correlation between Long RECK and triglycerides in CTR group and a positive correlation in the AMI group was found. The combined evaluation of Long and Short RECK expression levels is a potential genomic biomarker for the discrimination of AMI from CAD patients. Our results underline the relevance of deeper studies on the expression of these two splice variants to elucidate their functional role in CAD development and progression.


Assuntos
Processamento Alternativo , Doença da Artéria Coronariana/genética , Proteínas Ligadas por GPI/genética , Infarto do Miocárdio/genética , Idoso , Biomarcadores/metabolismo , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Projetos Piloto
2.
Biomed Pharmacother ; 139: 111621, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243599

RESUMO

Alterations in xanthine oxidase activity are known to be pathologically influential on coronary artery disease (CAD), but the association between purine-related blood metabolites and CAD has only been partially elucidated. We performed global metabolomics profiling and network analysis on blood samples from the Wonju and Pyeongchang (WP) cohort study (n = 2055) to elucidate the importance of purine related metabolites associated with potential CAD risk. Then, 5 selected serum metabolites were quantified from the WP cohort, Shinchon cohort (n = 259), and Shinchon case control (n = 424) groups to develop machine learning models for 10-year risk prediction, relapse within 10 years and diagnosis of the disease via 100 repeated 5-fold cross-validations of logistic models. The combination of purine metabolite levels or only xanthine levels in blood could be applied for machine learning model development for major adverse cardiac and cerebrovascular event (MACCE, cerebrovascular death, nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and stroke) risk prediction, relapse of MACCEs among patients with myocardial infarction history and diagnosis of stable CAD. In particular, our research provided initial evidence that blood xanthine and uric acid levels play different roles in the development of machine learning models for primary/secondary prevention or diagnosis of CAD. In this research, we determined that purine-related metabolites in blood are applicable to machine learning model development for CAD risk prediction and diagnosis. Also, our work advances current CAD biomarker discovery strategies mainly relying on clinical features; emphasizes the differential biomarkers in first/secondary prevention or diagnosis studies.


Assuntos
Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Purinas/metabolismo , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Intervenção Coronária Percutânea/métodos , Prognóstico , Medição de Risco/métodos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
4.
J Steroid Biochem Mol Biol ; 212: 105940, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119628

RESUMO

Due to the biochemical importance of cholesterol homeostasis in cardiovascular disease (CVD), this study was aimed to identify metabolic signatures of serum sterols according to atherosclerotic CVD severity. Biogically active free cholesterol and its 11 analogues in serum samples obtained from subjects who underwent cardiovascular intervention were quantitatively evaluated by gas chromatography-mass spectrometry (GCMS). Study groups were divided by 29 patients with stable angina (SA), 35 patients with acute coronary syndrome (ACS), and 41 controls. In all subjects, serum levels of cholesterol and its upstream precursors of 7-dehydrocholesterol, lathosterol, and lanosterol were closely associated with CVD risk factors, such as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio (r = 0.407 ∼ 0.684, P < 0.03 for all). Metabolic ratios of lathosterol/cholesterol (control = 55.75 ± 34.34, SA = 51.04 ± 34.93, ACS = 36.52 ± 22.00; P < 0.03) and lanosterol/cholesterol (control = 12.27 ± 7.43, SA = 10.97 ± 9.13, ACS = 8.01 ± 5.82; P < 0.03), were remarkably decreased. Both metabolic ratios and individual concentrations of lathosterol and lanosterol were also decreased in subjects with statin treatment than those in the control group without statin treatment (P < 0.05 for all), whereas three metabolic ratios of dietary sterols (sitosterol, campesterol, and stigmasterol) to free cholesterol were increased after statin therapy (P < 0.05 for all) in both SA and ACS groups. The present metabolic signatures suggest that both lathosterol/cholesterol and lanosterol/cholesterol ratios corresponding to cholesterol biosynthesis may reflect statin response. Individual dietary sterols to cholesterol ratios resulted in higher intestinal cholesterol absorption after statin therapy.


Assuntos
Doença da Artéria Coronariana/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Esteróis/biossíntese , Absorção Fisiológica , Adulto , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Dislipidemias/cirurgia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Esteróis/sangue
5.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073212

RESUMO

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as "wall shear stress (WSS)", and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.


Assuntos
Doença da Artéria Coronariana , Circulação Coronária , Células Endoteliais , Placa Aterosclerótica , Resistência ao Cisalhamento , Estresse Mecânico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Placa Aterosclerótica/terapia
6.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066314

RESUMO

HDL particles can be structurally modified in atherosclerotic disorders associated with low HDL cholesterol level (HDL-C). We studied whether the lipidome of the main phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) species of HDL2 and HDL3 subfractions is associated with premature coronary heart disease (CHD) or metabolic syndrome (MetS) in families where common low HDL-C predisposes to premature CHD. The lipidome was analyzed by LC-MS. Lysophosphatidylcholines were depleted of linoleic acid relative to more saturated and shorter-chained acids containing species in MetS compared with non-affected subjects: the ratio of palmitic to linoleic acid was elevated by more than 30%. A minor PC (16:0/16:1) was elevated (28-40%) in MetS. The contents of oleic acid containing PCs were elevated relative to linoleic acid containing PCs in MetS; the ratio of PC (16:0/18:1) to PC (16:0/18:2) was elevated by 11-16%. Certain PC and SM ratios, e.g., PC (18:0/20:3) to PC (16:0/18:2) and a minor SM 36:2 to an abundant SM 34:1, were higher (11-36%) in MetS and CHD. The fatty acid composition of certain LPCs and PCs displayed a characteristic pattern in MetS, enriched with palmitic, palmitoleic or oleic acids relative to linoleic acid. Certain PC and SM ratios related consistently to CHD and MetS.


Assuntos
Doença da Artéria Coronariana/metabolismo , Ácidos Graxos/metabolismo , Lipoproteínas HDL/metabolismo , Síndrome Metabólica/metabolismo , Fosfolipídeos/metabolismo , Adulto , Família , Feminino , Humanos , Lipidômica , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Adv Clin Chem ; 102: 233-270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34044911

RESUMO

Coronary artery disease (CAD), the most common cardiovascular disease (CVD), contributes to significant mortality worldwide. CAD is a multifactorial disease wherein various factors contribute to its pathogenesis often complicating management. Biomarker based personalized medicine may provide a more effective way to individualize therapy in multifactorial diseases in general and CAD specifically. Systems' biology "Omics" biomarkers have been investigated for this purpose. These biomarkers provide a more comprehensive understanding on pathophysiology of the disease process and can help in identifying new therapeutic targets and tailoring therapy to achieve optimum outcome. Metabolomics biomarkers usually reflect genetic and non-genetic factors involved in the phenotype. Metabolomics analysis may provide better understanding of the disease pathogenesis and drug response variation. This will help in guiding therapy, particularly for multifactorial diseases such as CAD. In this chapter, advances in metabolomics analysis and its role in personalized medicine will be reviewed with comprehensive focus on CAD. Assessment of risk, diagnosis, complications, drug response and nutritional therapy will be discussed. Together, this chapter will review the current application of metabolomics in CAD management and highlight areas that warrant further investigation.


Assuntos
Doença da Artéria Coronariana/metabolismo , Metabolômica , Medicina de Precisão , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Humanos
9.
Am J Med ; 134(9): 1091-1095, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34019857

RESUMO

In 2018, cardiovascular society cholesterol guidelines recommended the use of coronary artery calcium to guide statin therapy in patients 40-79 years of age who are at intermediate risk by multiple risk factor equations (ie, estimated 10-year risk for atherosclerotic disease of 7.5%-19.9% but in whom statin benefit is uncertain). Many such patients have no coronary calcium and remain at <5% risk over the next decade; hence, statin therapy can be delayed until a repeat calcium scan is conducted. Exceptions include patients with severe hypercholesterolemia, diabetes, and a strong family history of atherosclerotic disease. If coronary calcium equals 1-99 Agatston units, the 10-year risk is borderline (5% to <7.5%) and statin therapy is optional pending a repeat scan. If coronary calcium equals 100-299 Agatston units, the patient is clearly statin eligible (7.5% to <20% 10-year risk). And finally, if coronary calcium is ≥300 Agatston units, a patient is at high risk and is a candidate for high-intensity statins. Risk factor analysis combined judiciously with coronary calcium scanning offers the strongest evidence-based approach to use of statins in primary prevention.


Assuntos
Doença da Artéria Coronariana , Vasos Coronários/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Calcificação Vascular , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Prática Clínica Baseada em Evidências , Humanos , Seleção de Pacientes , Prevenção Primária/métodos , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/prevenção & controle
10.
Clin Biochem ; 93: 50-58, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861985

RESUMO

OBJECTIVE: C1q has been shown to be associated with coronary heart disease (CAD) and can co-deposit with C-reactive protein (CRP) in atherosclerotic plaques. However, few studies have been conducted between C1q, CRP parameters and CAD. The aim of this study is to explore the relationship between C1q and CRP parameters and assess their clinical significance in CAD. METHODS: 238 total patients who underwent coronary artery angiography were enrolled and divided into control group (n = 65), stable CAD group (n = 47) and unstable angina group (UA group, n = 126). Patients' data were collected from self-administered questionnaires and electrical medical records. The severity of coronary stenosis was presented by Gensini score. The relationship between C1q, CRP parameters and CAD were evaluated by multivariate regression analysis and their predicting performance were assessed by ROC analysis and odds ratio analysis. RESULTS: Compared with control group, C1q was showed significantly lower in stable CAD (P = 0.004) and UA groups (P = 0.008), while hsCRP was higher in UA group (P = 0.024). Serum C1q was weakly positively associated with hsCRP (r = 0.24, P < 0.001) but not correlated with Gensini score. Logistic regression identified C1q (OR: 0.87 per 10 mg/L, 95% CI: 0.79-0.95, P = 0.001) and hsCRP (OR: 1.08 mg/L, 95% CI: 1.01-1.15, P = 0.032) as independent determinants of CAD. Furthermore, combined C1q and hsCRP level showed higher discriminatory accuracy in predicting CAD than C1q (AUC: 0.676 vs 0.585, P = 0.101; NRI: 10.4%, P = 0.049; IDI: 3.9%, P < 0.001) or hsCRP (AUC: 0.676 vs 0.585, P = 0.101; NRI: 16.7%, P = 0.006; IDI: 5.8%, P < 0.001). CONCLUSIONS: Reduced serum C1q and increased hsCRP are independently associated with CAD and could be potential predictors for CAD diagnosis. Furthermore, combined C1q and hsCRP showed better performance in predicting CAD than using single one.


Assuntos
Proteína C-Reativa/metabolismo , Complemento C1q/metabolismo , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Idoso , Angina Instável/diagnóstico , Angina Instável/metabolismo , Biomarcadores/sangue , Angiografia Coronária , Estenose Coronária/diagnóstico , Estenose Coronária/metabolismo , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Curva ROC , Fatores de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas
11.
FASEB J ; 35(5): e21609, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33908659

RESUMO

Our purpose was to study the effect of hyperglycemia on macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling and its correlation with coronary atherosclerosis. A total of 135 patients with coronary heart disease (CHD) were divided into a stable CHD (SCHD) group (n = 30) and an acute myocardial infarction (AMI) group (n = 105) [nondiabetes mellitus (non-DM)-AMI, n = 60; DM-AMI, n = 45] from January to September 2020. The SYNTAX score and metabolic and inflammatory markers were quantified and compared. THP-1 cell studies and an animal study of coronary intimal hyperplasia were also carried out. We found that the DM-AMI group showed a higher SYNTAX score than the non-DM-AMI group (P < .05). The DM-AMI group showed the highest expression levels of TANK-binding kinase 1 (TBK1), hypoxia-inducible factor 1α (HIF-1α), and interleukin (IL)-17 and the lowest expression level of IL-10, followed by the non-DM-AMI group and the SCHD group (P < .05). THP-1 cell studies showed that BAY87-2243 (a HIF-1α inhibitor) reversed the increase in IL-17 and decrease in IL-10 expression induced by hyperglycemia. Amlexanox (a TBK1 inhibitor) reversed the increase in HIF-1α expression induced by hyperglycemia. Amlexanox treatment resulted in lower coronary artery intimal hyperplasia and a larger lumen area in a diabetic swine model. We conclude that hyperglycemia might aggravate the complexity of coronary atherosclerosis through activation of TBK1-HIF-1α-mediated IL-17/IL-10 signaling. Thus, TBK1 may be a novel drug therapy target for CHD complicated with DM.


Assuntos
Doença da Artéria Coronariana/patologia , Hiperglicemia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Macrófagos/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Idoso , Animais , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Técnicas In Vitro , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Suínos
12.
Am J Physiol Heart Circ Physiol ; 320(6): H2222-H2239, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33834866

RESUMO

Extracellular matrix (ECM) exerts a series of biological functions and contributes to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the role of periostin in vascular calcification has yet to be fully investigated. As found in this study, recombinant periostin accelerated the thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS) ex vivo, which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition and suppressed PPARγ expression. Mechanistically, periostin caused overactivation of glycolysis and mitochondrial dysfunction in VSMCs as assessed by extracellular acidification rate, oxygen consumption rate, and mitochondrial respiratory chain complex activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients undergoing computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score in patients with coronary artery calcification (CAC). There was also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.NEW & NOTEWORTHY Periostin caused arterial calcification, overactivated glycolysis, and damaged OXPHOS. PPARγ agonists alleviated periostin-promoted arterial calcification and corrected abnormal glycolysis and unbalanced mitochondrial homeostasis. There exists a relationship between periostin and lactate in patients with CAC.


Assuntos
Aorta Torácica/metabolismo , Moléculas de Adesão Celular/metabolismo , Doença da Artéria Coronariana/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Miócitos de Músculo Liso/metabolismo , PPAR gama/metabolismo , Calcificação Vascular/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/farmacologia , Angiografia por Tomografia Computadorizada , Regulação para Baixo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ácido Láctico/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio , PPAR gama/agonistas , Pioglitazona/farmacologia , Ratos
13.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917744

RESUMO

Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.


Assuntos
Biomarcadores , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Vasculite/etiologia , Vasculite/metabolismo , Animais , Permeabilidade Capilar , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/fisiopatologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Hemostasia , Humanos , Terapia de Alvo Molecular/métodos , Vasculite/tratamento farmacológico , Vasculite/fisiopatologia
14.
Nutr Metab Cardiovasc Dis ; 31(5): 1349-1356, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812732

RESUMO

AIM: Coronary artery bypass graft (CABG) using autologous saphenous vein continues to be a gold standard procedure to restore the supply of oxygen-rich blood to the heart muscles in coronary artery disease (CAD) patients with or without type 2 diabetes mellitus (T2DM). However, CAD patients with T2DM are at higher risk of graft failure. While failure rates have been reduced through improvements in procedure-related factors, much less is known about the molecular and cellular mechanisms by which T2DM initiates vein graft failure. This review gives novel insights into these cellular and molecular mechanisms and identifies potential therapeutic targets for development of new medicines to improve vein graft patency. DATA SYNTHESIS: One important cellular process that has been implicated in the pathogenesis of T2DM is protein O-GlcNAcylation, a dynamic, reversible post-translational modification of serine and threonine residues on target proteins that is controlled by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Protein O-GlcNAcylation impacts a range of cellular processes, including trafficking, metabolism, inflammation and cytoskeletal organisation. Altered O-GlcNAcylation homeostasis have, therefore, been linked to a range of human pathologies with a metabolic component, including T2DM. CONCLUSION: We propose that protein O-GlcNAcylation alters vascular smooth muscle and endothelial cell function through modification of specific protein targets which contribute to the vascular re-modelling responsible for saphenous vein graft failure in T2DM.


Assuntos
Glicemia/metabolismo , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Diabetes Mellitus Tipo 2/complicações , Oclusão de Enxerto Vascular/etiologia , Processamento de Proteína Pós-Traducional , Veia Safena/transplante , Animais , Biomarcadores/sangue , Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicosilação , Oclusão de Enxerto Vascular/metabolismo , Oclusão de Enxerto Vascular/patologia , Oclusão de Enxerto Vascular/prevenção & controle , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Medição de Risco , Fatores de Risco , Veia Safena/metabolismo , Veia Safena/patologia , Falha de Tratamento , Remodelação Vascular
15.
Gene ; 788: 145669, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33882321

RESUMO

The current work focused on evaluating the roles of endothelial lipase gene (LIPG) related single nucleotide polymorphisms (SNPs) in patients with coronary artery disease (CAD). This study involved 1,883 subjects with 959 CAD patients and 924 healthy controls. Data were harvested to assess the association of LIPG related SNPs including rs3744841, rs3744843, rs3813082 and rs2000813 with the risk of CAD. The CC + AC genotype in rs3813082 played a protective role for CAD [odds ratio (OR) = 0.709, P = 0.039]. Differences existed in apolipoprotein-A1 (Apo-A1) and high-density lipoprotein-cholesterol (HDL-C) levels in rs3744843 variant between control and CAD groups. The rs3744841 variant increased the levels of total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C), Apo-A1 and Lipoprotein a (LPa) in the CAD group and TC, LDL-C, HDL-C, Apo-B, Apo-A1 in the control group. The triglyceride (TG) level was lower in rs2000813 variant in the CAD group and elevated in the control group. The rs2000813 variant decreased the number of vascular stenosis while rs3744843 and rs3744841 variants increased the number of vascular stenosis in CAD patients. This study explored the roles of LIPG related SNPs in CAD, showing that CC + AC genotype in rs3813082 was a protective factor for CAD. The rs3744843, rs3744841 and rs2000813 variants were associated with the levels of lipid parameters in CAD patients. The rs3744843, rs3744841 and rs2000813 variants influenced the number of vascular stenosis in CAD patients. The results of our study might be a promising reference for preventing CAD.


Assuntos
Doença da Artéria Coronariana/genética , Lipase/genética , Polimorfismo de Nucleotídeo Único , Idoso , Apolipoproteína A-I/metabolismo , Estudos de Casos e Controles , China , HDL-Colesterol/metabolismo , Doença da Artéria Coronariana/metabolismo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade
16.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923232

RESUMO

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.


Assuntos
Coagulação Sanguínea , Doença da Artéria Coronariana/patologia , Proteínas de Membrana/metabolismo , Infarto do Miocárdio/patologia , Trombose/patologia , Doença da Artéria Coronariana/metabolismo , Humanos , Infarto do Miocárdio/metabolismo , Trombose/metabolismo
20.
Int Heart J ; 62(2): 371-380, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33731513

RESUMO

Coronary artery disease (CAD) is one of the heavy health burdens worldwide. Aberrant proliferation of vascular smooth muscle cells (VSMCs) contributes to the occurrence and development of CAD. This study aimed at exploring differentially expressed microRNAs (miRNAs) and their regulatory mechanisms in the development of CAD.The miRNA expression profile of GSE28858 was obtained from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEmiRNAs) between CAD and healthy control samples were analyzed using limma package in R. Target genes of DEmiRNAs were predicted, and a miRNA-target gene network was constructed. The relationship between miR-665 and transforming growth factor beta receptor 1 (TGFBR1) was selected for further analysis. The interaction between miR-665 and TGFBR1 was confirmed by dual luciferase reporter assay. Effects of miR-665 on cell viability and apoptosis of VSMCs were evaluated by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Besides, western blot assays for BCL2L11 and caspase 3 were also conducted.A total of 38 upregulated miRNAs and 28 downregulated miRNAs were identified. The expression level of miR-665 was significantly downregulated in patients with CAD. TGFBR1 was proved to be a target gene of miR-665. Besides, ectopic expression of miR-665 obviously inhibited VSMC growth and promoted VSMC apoptosis. TGFBR1 overexpression in VSMCs transfected with miR-665 mimic could restore the effect of miR-665 on the proliferation and apoptosis of VSMCs.MiR-665 might participate in the proliferation and apoptosis of VSMCs by targeting TGFBR1.


Assuntos
Doença da Artéria Coronariana/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Miócitos de Músculo Liso/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Regulação para Baixo , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Miócitos de Músculo Liso/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/biossíntese , Regulação para Cima
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