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2.
bioRxiv ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33300001

RESUMO

Coronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.

3.
BMC Cardiovasc Disord ; 20(1): 441, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032539

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

4.
JCI Insight ; 5(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33119548

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects cholesterol homeostasis by targeting hepatic LDL receptor (LDLR) for lysosomal degradation. Clinically, PCSK9 inhibitors effectively reduce LDL-cholesterol (LDL-C) levels and the incidence of cardiovascular events. Because microRNAs (miRs) are integral regulators of cholesterol homeostasis, we investigated the involvement of miR-483 in regulating LDL-C metabolism. Using in silico analysis, we predicted that miR-483-5p targets the 3'-UTR of PCSK9 mRNA. In HepG2 cells, miR-483-5p targeted the PCSK9 3'-UTR, leading to decreased PCSK9 protein and mRNA expression, increased LDLR expression, and enhanced LDL-C uptake. In hyperlipidemic mice and humans, serum levels of total cholesterol and LDL-C were inversely correlated with miR-483-5p levels. In mice, hepatic miR-483 overexpression increased LDLR levels by targeting Pcsk9, with a significant reduction in plasma total cholesterol and LDL-C levels. Mechanistically, the cholesterol-lowering effect of miR-483-5p was significant in mice receiving AAV8 PCSK9-3'-UTR but not Ldlr-knockout mice or mice receiving AAV8 PCSK9-3'-UTR (ΔBS) with the miR-483-5p targeting site deleted. Thus, exogenously administered miR-483 or similarly optimized compounds have potential to ameliorate hypercholesterolemia.

5.
BMC Cardiovasc Disord ; 20(1): 409, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912149

RESUMO

BACKGROUND: Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with its incidence markedly declined in the recent decades. However, clinical features of CR patients now and the effect of reperfusion therapy to CR remain unclear. We investigated the clinical features of CR in STEMI patients and the effect of reperfusion therapy to CR in mice. METHODS: Two studies were conducted. In clinical study, data of 1456 STEMI patients admitted to the First Hospital, Xi'an Jiaotong University during 2015.12. ~ 2018.12. were analyzed. In experimental study, 83 male C57BL/6 mice were operated to induce MI. Of them, 39 mice were permanent MI (group-1), and remaining mice received reperfusion after 1 h ischemia (21 mice, group-2) or 4 h ischemia (23 mice, group-3). All operated mice were monitored up to day-10. Animals were inspected three times daily for the incidence of death and autopsy was done for all mice found died to determine the cause of death. RESULTS: CR was diagnosed in 40 patients: free-wall rupture in 17, ventricular septal rupture in 20, and combined locations in 3 cases. CR presented in 19 patients at admission and diagnosed in another 21 patients during 1 ~ 14 days post-STEMI, giving an in-hospital incidence of 1.4%. The mortality of CR patients was high during hospitalization accounting for 39% of total in-hospital death. By multivariate logistic regression analysis, older age, peak CK-MB and peak hs-CRP were independent predictors of CR post-STEMI. In mice with non-reperfused MI, 17 animals (43.6%) died of CR that occurred during 3-6 days post-MI. In MI mice received early or delayed reperfusion, all mice survived to the end of experiment except one mouse died of acute heart failure. CONCLUSION: CR remains as a major cause of in-hospital death in STEMI patients. CR patients are characterized of being elderly, having larger infarct and more server inflammation. Experimentally, reperfusion post-MI prevented CR.

6.
Eur J Clin Nutr ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994554

RESUMO

BACKGROUND/OBJECTIVES: Chronic kidney disease (CKD) is a global public health problem, including in China. The aim of this study was to identify the risk factors for the development and progression of subclinical renal disease (SRD) in a Chinese population. We also examined whether the impact of the risk factors on SRD changed over time. SUBJECTS/METHODS: To identify the predictors of SRD, we performed a cross-sectional study of the 2432 subjects in our Hanzhong Adolescent Hypertension Cohort. A subgroup of 202 subjects was further analyzed over a 12-year period from 2005 to 2017 to determine the risk factors for the development and progression of SRD. RESULTS: In cross-sectional analysis, elevated blood pressure, male gender, diabetes, body mass index, and triglyceride were independently associated with a higher risk of SRD. In longitudinal analysis, an increase in total cholesterol over a 4-year period and an increase in serum triglyceride over a 12-year period were independently associated with progression of albuminuria. Finally, increases in both total cholesterol and serum uric acid over a 4-year follow-up showed an independent association with a modest reduction in estimated glomerular filtration rate (eGFR). CONCLUSIONS: In this study of a Chinese cohort, we show several metabolic abnormalities as independent risk factors for subclinical renal disease in a Chinese cohort. In addition, we demonstrate that the effects of total cholesterol, triglycerides and uric acid on the development and progression of albuminuria or the decline in eGFR vary at different points of follow-up. These findings highlight the importance of early detection of metabolic abnormalities to prevent SRD.

7.
Circulation ; 142(12): 1190-1204, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32755395

RESUMO

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1-7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH. METHODS: Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH. RESULTS: Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH. CONCLUSIONS: Maladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.


Assuntos
Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Hipertensão Arterial Pulmonar/patologia , Ubiquitinação , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/genética , Animais , Suscetibilidade a Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos
8.
Med Clin (Barc) ; 2020 Jul 16.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32684295

RESUMO

BACKGROUND: Atrial fibrillation (AF) has the close relation to thyroid dysfunction and these two diseases lead to poor cardiovascular outcomes. But the prognostic value of thyroid diseases in AF remains unclear. We aimed to determine whether history of thyroid diseases is associated with risk of in-hospital cardiovascular outcomes in AF. METHODS: Based on the data from the CCC-AF (Improving Care for Cardiovascular Diseases in China-Atrial Fibrillation) project, 31,486 inpatients with a definitive diagnosis of AF and record of history of thyroid diseases were included. Logistic regression analysis was performed to investigate the relationship between history of thyroid diseases and risk of in-hospital major adverse cardiovascular events (MACE) in AF. RESULTS: Among AF patients, 503 (1.6%) had a history of hypothyroidism, 642 (2.0%) had a history of hyperthyroidism and 30,341 (96.4%) had no thyroid dysfunction. During this hospitalization, 5146 (16.3%) AF patients suffered from MACE. The incidence was 13.1% in hypothyroidism, 16.3% in euthyroidism and 19.0% in hyperthyroidism, in which there was a significant difference among three groups (p=0.028). Multivariable logistic regression analysis revealed that history of hypothyroidism decreased but history of hyperthyroidism increased the risk of in-hospital MACE in AF patients (adjusted odds ratio [OR]=0.603; 95% confidence interval [CI], 0.449-0.811; p=0.001 versus adjusted OR=1.327; 95% CI, 1.060-1.661; p=0.013). CONCLUSION: History of hypothyroidism was an independent protective factor, whereas history of hyperthyroidism was an independent risk factor for in-hospital cardiovascular outcomes in AF. Our study indicated that hyperthyroidism should be treated aggressively in order to improve the prognosis of AF.

9.
J Geriatr Cardiol ; 17(5): 246-255, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32547607

RESUMO

Objective: To describe the long-term antithrombotic management patterns (AMPs) and clinical outcomes of Chinese patients with acute coronary syndrome (ACS). Methods: This was an observational, multicenter, longitudinal cohort extension study of Chinese patients who had completed the EPICOR Asia 2-year follow-up study post-hospitalization for an ACS event. Changes in AMP and clinical outcomes for up to 5 years post-ACS event were evaluated. Results: Overall, 2334 patients with ACS were enrolled at 49 sites. The mean age was 61.6 years and 76.3% were men. By study end, 2093 patients completed the 3-year follow-up. At baseline (2 years post-ACS event), 72.4% of patents received one antiplatelet (AP) medication, with aspirin being the preferred one. A small proportion of patients (21.5%) was treated with two or more APs (2+ AP), and even fewer patients (6.1%) did not receive any AP medication at baseline. Upon study completion, the proportion of patients without AP therapy increased to 13.6%, while the percentage of patients on one AP and 2+ AP decreased to 69.3% and 17.1%, respectively. Numerically, a higher incidence of clinical events (composite of all-cause mortality, myocardial infarction, stroke) was observed for the 2+ AP (13.2%) subgroup than for the no AP (10.5%) and one AP (8.6%) subgroups. Furthermore, the 2+ AP subgroup exhibited the greatest number of bleeding events, outpatient visits, and hospitalization rates. Unlike myocardial infarction or stroke, bleeding events prompted an adjustment in AMP. Conclusion: Most patients in China received at least one AP medication up to 5 years after an ACS event.

10.
Am J Physiol Cell Physiol ; 317(4): C776-C787, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390228

RESUMO

Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK+CD68+double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT1R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients.


Assuntos
Proteína ADAM17/efeitos dos fármacos , Angiotensina II/farmacologia , Aterosclerose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , c-Mer Tirosina Quinase/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Transgênicos , Fagocitose/efeitos dos fármacos , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Trials ; 20(1): 335, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174600

RESUMO

BACKGROUND: Earlier vascular healing after drug-eluting stent (DES) implantation may reduce the incidence of late stent thrombosis and provide theoretical evidence to shorten dual antiplatelet therapy duration in patients with high bleeding risks. The BuMA supreme stent is a newly developed DES-coated with the sirolimus by using the international patent electronic grafted eG™ technology. Previous randomized trials showed that BuMA stents had better stent-strut coverage at 3-month follow-ups, which were evaluated by optical coherence tomography (OCT). However, there have been a limited number of studies that are directly evaluating the extent of neointima formation at the first and second months after stent implantation in high-bleeding-risk patients with coronary artery disease. This clinical trial is designed to demonstrate the non-inferiority of the BuMA supreme stent compared to the XIENCE stent in early neointimal formation. METHODS/DESIGN: This is a prospective, multicenter, randomized trial. Forty patients will be assigned into the first-month OCT group, and another 40 patients into the second-month OCT group. The patients in each cohort will be randomized again into two groups in a 1:1 ratio, either being implanted with the BuMA Supreme stent or the Xience V/Prime/Xpedition stent. The primary endpoint is stent-strut neointimal coverage rate (%) at the first and second months, respectively. Secondary endpoints include neointimal hyperplasia area/volume, neointimal hyperplasia thickness, stent-strut malapposition rate, late lumen loss (LLL), restenosis rate, device/lesion/clinical success rate, device-oriented composite endpoints at the first and second months, stent thrombosis and other serious adverse events and bleeding events at follow-up. DISCUSSION: The results will provide the first accurate imaging evidence on neointimal formation of the BuMA Supreme stent and the Xience stent at 1-2 months post PCI. The result should inspire further exploration and adjustment of DAPT treatments. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02747329 . Registered on 21 April 2016. Last updated 17 May 2018.


Assuntos
Doença da Artéria Coronariana/terapia , Vasos Coronários/diagnóstico por imagem , Stents Farmacológicos , Neointima , Intervenção Coronária Percutânea/instrumentação , Tomografia de Coerência Óptica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico por imagem , Estudos de Equivalência como Asunto , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Desenho de Prótese , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
12.
J Hypertens ; 37(6): 1167-1175, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026243

RESUMO

OBJECTIVE: Atherosclerotic diseases are the leading cause of death worldwide. This study aimed to investigate the predictors of brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (CIMT) progression in a Chinese cohort over a 12-year follow-up period and to determine whether these predictors differ by follow-up time. METHODS: A total of 202 participants were recruited from a previously established cohort in Shaanxi Province, China. Both baPWV and CIMT were measured in 2013 and 2017. Multivariable regression was used to determine the predictors of CIMT and baPWV progression. RESULTS: Men had higher CIMT and baPWV and a higher rate of CIMT progression during two follow-ups than women. A 4-year change in SBP was associated with baPWV progression, whereas a 12-year change in DBP was associated with baPWV progression. The increased progression of baPWV presented a linear trend when subgrouping all the participants according to SBP and DBP changes over 4 and 12 years, respectively. In addition, heart rate (HR) change over 4 and 12 years was consistently associated with CIMT progression, and a linear trend was also seen when subgrouping the population. CONCLUSION: Our study demonstrated that SBP and DBP contributed differently in different stages to the progression of arterial stiffness in this Chinese cohort. Moreover, HR was consistently involved in the increased progression of CIMT in all periods. These findings underline the importance of early detection and control of blood pressure and resting HR for the prevention of arterial stiffness progression.


Assuntos
Pressão Sanguínea , Espessura Intima-Media Carotídea , Análise de Onda de Pulso , Rigidez Vascular/fisiologia , Adulto , Índice Tornozelo-Braço , Grupo com Ancestrais do Continente Asiático , Aterosclerose/fisiopatologia , China , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Frequência Cardíaca , Humanos , Hipertensão/fisiopatologia , Masculino
13.
Thromb Res ; 170: 142-147, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193195

RESUMO

INTRODUCTION: Both Global Registry of Acute Coronary Events (GRACE) risk score and CYP2C19 metabolizer status can independently predict major adverse cardiac events (MACEs) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We investigated whether their combination could better predict MACE occurrence in patients with ACS undergoing PCI. MATERIALS AND METHODS: This retrospective cohort study included 548 consecutive patients with ACS undergoing PCI. A cumulative MACE curve was calculated using the Kaplan-Meier method. Multivariate Cox regression was used to identify MACE predictors. The predictive value of GRACE risk score alone and CYP2C19 metabolizer status was estimated by the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: In a median of 28.58 months, 17 patients (3%) were lost to follow-up, and 62 (11.3%) experienced MACEs. Multivariate Cox regression analysis showed that both GRACE score and CYP2C19 metabolizer status were independent MACE predictors (hazard ratio 1.019, 95% CI 1.011-1.027, p < 0.001; hazard ratio 2.383, 95% CI 1.601-3.547, p < 0.001, respectively). Kaplan-Meier analysis showed that CYP2C19 PM increased the MACE risk (log rank test = 10.848, p = 0.004). The GRACE score adjustment by CYP2C19 metabolizer status enhanced the predictive value (AUC increased from 0.682 for GRACE score alone to 0.731 for GRACE score plus CYP2C19 metabolizer). This result was further verified by IDI and NRI. CONCLUSIONS: CYP2C19 metabolizer status and GRACE score are readily available predictive approaches for MACEs, and their combination derives a more accurate long-term MACE prediction in clopidogrel-treated patients with ACS undergoing PCI.


Assuntos
Síndrome Coronariana Aguda/genética , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea/métodos , Síndrome Coronariana Aguda/patologia , Idoso , Estudos de Coortes , Citocromo P-450 CYP2C19/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
14.
Sci Rep ; 8(1): 7749, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773847

RESUMO

High uric acid (UA) level and high salt intake are reportedly associated with cardiovascular disease. This study investigated the association between UA and urinary sodium excretion, as well as its interaction on the risk of prehypertension. A total of 1869 participants without hypertension were recruited from a previously established cohort in Shaanxi Province, China. The participants were classified as normotensive or prehypertensive on the basis of their blood pressure. Increasing quartiles of sodium excretion were associated with high urinary UA/creatinine levels in prehypertensive participants. Estimated sodium excretion positively correlated with urinary UA/creatinine excretions in the prehypertensive group. In addition, the multivariate-adjusted odds ratios for prehypertension compared with normotension were 1.68 (1.27-2.22) for sodium excretion and 1.71 (1.21-2.42) for serum UA. Increasing sodium excretion and serum UA were associated with higher risk of prehypertension. Compared with the lowest quartiles, the highest sodium excretion and serum UA quartiles entailed 3.48 times greater risk of prehypertension. Sodium excretion is associated with urinary UA excretion in prehypertensive participants. The present study shows that high levels of salt intake and serum UA simultaneously are associated with a higher risk of prehypertension.


Assuntos
Pré-Hipertensão/diagnóstico , Pré-Hipertensão/epidemiologia , Sódio/metabolismo , Ácido Úrico/metabolismo , Adulto , Pressão Sanguínea , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Hipertensão/etiologia , Pré-Hipertensão/metabolismo , Prognóstico , Fatores de Risco , Adulto Jovem
15.
Am J Respir Crit Care Med ; 198(4): 509-520, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29570986

RESUMO

RATIONALE: Endothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive. OBJECTIVES: We investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH. METHODS: Bioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE2-/-) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Phosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPKα2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension. CONCLUSIONS: Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Animais , Modelos Animais de Doenças , Endotélio Vascular/enzimologia , Humanos , Hipertensão Pulmonar/enzimologia , Pulmão/enzimologia , Pulmão/fisiopatologia , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley
16.
Sci Rep ; 8(1): 1434, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362390

RESUMO

Uric acid (UA) has been proposed as an important risk factor for cardiovascular and renal morbidity. We conducted an interventional trial to assess effects of altered salt intake on plasma and urine UA levels and the relationship between UA levels and salt sensitivity in humans. Ninety subjects (18-65 years old) were sequentially maintained on a normal diet for 3 days at baseline, a low-salt diet for 7 days (3.0 g/day, NaCl), and a high-salt diet for an additional 7 days (18.0 g/day of NaCl). Plasma UA levels significantly increased from baseline to low-salt diet and decreased from low-salt to high-salt diet. By contrast, daily urinary levels of UA significantly decreased from baseline to low-salt diet and increased from low-salt to high-salt diet. The 24 h urinary sodium excretions showed inverse correlation with plasma UA and positive correlation with urinary UA excretions. Additionally, salt-sensitive subjects presented significantly higher plasma UA changes in comparison to salt-resistant subjects, and a negative correlation was observed between degree of salt sensitivity and plasma UA difference. The present study indicates that variations in dietary salt intake affect plasma and urine UA levels, and plasma UA may be involved in pathophysiological process of salt sensitivity.


Assuntos
Cloreto de Sódio na Dieta/administração & dosagem , Ácido Úrico/sangue , Ácido Úrico/urina , Adulto , Grupo com Ancestrais do Continente Asiático , Dieta Hipossódica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sódio/urina , Cloreto de Sódio na Dieta/farmacologia
17.
Br J Pharmacol ; 175(8): 1305-1317, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28409833

RESUMO

BACKGROUND AND PURPOSE: Our recent studies show that the reduced activity of epithelial sodium channels (ENaC) in endothelial cells accounts for the adaptation of vasculature to salt in Sprague-Dawley rats. The present study examines a hypothesis that enhanced ENaC activity mediates the loss of vasorelaxation in Dahl salt-sensitive (SS) rats. EXPERIMENTAL APPROACH: We used the cell-attached patch-clamp technique to record ENaC activity in split-open mesenteric arteries. Western blot and immunofluorescence staining were used to evaluate the levels of aldosterone, ENaC, eNOS and NO. Blood pressure was measured with the tail-cuff method and the artery relaxation was measured with the wire myograph assay. KEY RESULTS: High-salt (HS) diet significantly increased plasma aldosterone and ENaC activity in the endothelial cells of Dahl SS rats. The endothelium-dependent artery relaxation was blunted by HS challenge in these rats. Amiloride, a potent blocker of ENaC, increased both phosphorylated eNOS and NO and therefore prevented the HS-induced loss of vasorelaxation. As, in SS rats, endogenous aldosterone was already elevated by HS challenge, exogenous aldosterone did not further elevate ENaC activity in the rats fed with HS. Eplerenone, a mineralocorticoid receptor antagonist, attenuated the effects of HS on both ENaC activity and artery relaxation. CONCLUSIONS AND IMPLICATIONS: These data suggest that HS diet blunts artery relaxation and causes hypertension via a pathway associated with aldosterone-dependent activation of ENaC in endothelial cells. This pathway provides one of the mechanisms by which HS causes hypertension in Dahl SS rats. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.


Assuntos
Células Endoteliais/efeitos dos fármacos , Agonistas do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/fisiologia , Cloreto de Sódio na Dieta/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/fisiologia , Masculino , Artérias Mesentéricas/citologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos Dahl , Vasodilatação/efeitos dos fármacos
18.
Am J Hypertens ; 31(2): 253-260, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28985241

RESUMO

BACKGROUND: Dietary sodium and potassium affect the fluctuation in blood pressure (BP) and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates BP, cardiac, and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance. METHODS: Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3.0 g/day NaCl), a HS diet (18.0 g/day NaCl), followed by an HS diet with K+ supplementation (HS + K+) (18.0 g/day NaCl and 4.5 g/day KCl). RESULTS: Corin level was higher with the HS diet than the LS and HS + K+ diets and was positively correlated with systolic BP (SBP) and 24-hour urinary Na+ and microalbumin (U-mALB) excretion. In rodents, serum and renal levels of corin were transiently increased with the HS diet and were decreased if the HS diet was continued for up to 7 days. HS loading increased SBP, 24-hour urinary Na+, U-mALB excretion, and the expression of proprotein convertase subtilisin/kexin-6 (PCSK6), a corin activator. Knockdown of PCSK6 or corin in high salt-treated M1-cortical collecting duct (M1-CCD) cells increased the expression of aquaporin 2 (AQP2) and ß-epithelial Na+ channel (ß-ENaC). CONCLUSIONS: Short-term HS may induce the PCSK6-corin-ANP-AQP2/ß-ENaC pathway in the kidney. Enhanced serum corin level in humans and rodents is positively correlated with HS-induced SBP and 24-hour urinary Na+ and U-mALB excretion, which suggests that corin is involved in the salt-water balance in response to HS intake. CLINICAL TRIALS REGISTRATION: Public Trials Registry Number NCT02915315.


Assuntos
Dieta Hipossódica , Rim/enzimologia , Potássio na Dieta/administração & dosagem , Serina Endopeptidases/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Equilíbrio Hidroeletrolítico , Adaptação Fisiológica , Adulto , Albuminúria/enzimologia , Albuminúria/fisiopatologia , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Pressão Sanguínea , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Feminino , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Natriurese , Potássio na Dieta/efeitos adversos , Potássio na Dieta/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Ratos Sprague-Dawley , Serina Endopeptidases/genética , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio na Dieta/metabolismo , Fatores de Tempo , Regulação para Cima
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 37(8): 1003-1009, 2017 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-28801277

RESUMO

OBJECTIVE: To examine whether transforming growth factor-ß (TGF-ß) pathway and adaptive T cell immunity play roles in the anti-atherosclerotic effects of pioglitazone (PIO) in ApoE-/- mice. METHODS: ApoE-/- mice with atherosclerosis induced by high-fat feeding were treated daily with PIO (20 mg/kg) or vehicle for 8 weeks. The protein expressions of TGF-ß pathway in the atheromatous lesions of the aorta and the percentages of IFN-γ+ and Foxp3+ cells in the spleen of the mice were examined with immunohistochemical staining. In the in vitro experiment, primary cultured splenocytes were stimulated with oxidized low-density lipoproteins (oxLDL) and treated with PIO either alone or in combination with the PPARγ antagonist GW9662, after which the changes in percentages of CD4+IFN-γ+ cells and CD4+CD25+Foxp3+ cells were analyzed with flow cytometry. RESULTS: PIO treatment of ApoE-/- mice with high-fat feeding significantly attenuated the progression of atheromatous lesions (P<0.05) and resulted in increased expressions of TGFß1 (P<0.01), TGFßRII (P<0.05), and p-Smad3 (P<0.05) and a decreased expression of Smad7 (P<0.05) in the lesions. PIO treatment also led to decreased percentage of IFN-γ+ cells (P<0.05) and increased percentage of Foxp3+ cells (P<0.01) in the spleen of the mice. In primary cultured splenocytes, PIO treatment caused significant down-regulation of IFN-γ mRNA (P<0.05) and up-regulation of Foxp3 mRNA (P<0.05) and obviously increased the percentages of CD4+IFN-γ+ cells (P<0.05) and CD4+CD25+Foxp3+ (P<0.05); the effects of PIO on CD4+IFN-γ+ and CD4+CD25+Foxp3+ cells were abolished by treatment of the cells with GW9662. CONCLUSION: The anti-atherosclerotic effect of PIO is probably mediated by the TGF-ß/Smad signaling pathway and PPAR-γ-dependent modulation of Th1/Treg population.

20.
Nan Fang Yi Ke Da Xue Xue Bao ; 37(8): 1022-1027, 2017 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-28801280

RESUMO

OBJECTIVE: To investigate clinical implications of changes in red cell distribution width (RDW) and mean platelet volume (MPV) in patients with acute myocardial infarction. METHODS: A total of 127 patients (90 men and 37 women) were enrolled in this analysis, including 66 with acute myocardial infarction (AMI) and 61 with unstable angina (UA). The patients' baseline demographic and clinical data were compared between the two groups including age, hypertension, diabetes, smoking, BMI, blood biochemical profiles, cardiac functions and platelet and red blood cell parameters. The patients were further divided into subgroups according to the RDW 50% cumulative frequency, and the MPV, P-LCR, hsCRP, NT-proBNP, RBC, Dimer and MCV were compared. The correlations between platelet and erythrocyte test results were evaluated in both the AMI and UA patients. Regression analysis was performed to identify the factors affecting the RDW in the AMI group and a regression model was established. RESULTS: The platelet and red blood cell test results, P-LCR, MPV, and RDW differed significantly between AMI and UA groups (P<0.01 or 0.05). Correlation analysis showed a significant positive correlation between RDW and MPV in AMI group (r=0.34, P<0.01). Between the subgroups with different RDW 50% cumulative frequencies, MPV, P-LCR, hsCRP, D-Dimer, and NT-proBNP all differed significantly (P<0.05 or 0.01). In AMI group, with RDW as the dependent variable, we established a multivariate regression model of RDW=0.19MPV+10.83. CONCLUSION: RDW and MPV are closely correlated in patients with AMI. In multiple regression analysis, MPV can explain the changes in RDW in patients with AMI.

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