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1.
FASEB J ; 37(11): e23214, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37773768

RESUMEN

Atg2 is a key gene in autophagy formation and plays an important role in regulating aging progress. Exercise is an important tool to resist oxidative stress in cells and delay muscle aging. However, the relationship between exercise and the muscle Atg2 gene in regulating skeletal muscle aging remains unclear. Here, overexpression or knockdown of muscle Atg2 gene was achieved by constructing the AtgUAS/MhcGal4 system in Drosophila, and these flies were also subjected to an exercise intervention for 2 weeks. The results showed that both overexpression of Atg2 and exercise significantly increased the climbing speed, climbing endurance, cardiac function, and lifespan of aging flies. They also significantly up-regulated the expression of muscle Atg2, AMPK, Sirt1, and PGC-1α genes, and they significantly reduced muscle malondialdehyde and triglyceride. These positive benefits were even more pronounced when the two were combined. However, the effects of Atg2 knockdown on skeletal muscle, heart, and lifespan were reversed compared to its overexpression. Importantly, exercise ameliorated age-related changes induced by Atg2 knockdown. Therefore, current results confirmed that both overexpression of muscle Atg2 and exercise delayed age-related deteriorations of skeletal muscle, the heart function, and lifespan, and exercise could also reverse age-related changes induced by Atg2 knockdown. The molecular mechanism is related to the overexpression of the Atg2 gene and exercise, which increase the activity of the AMPK/Sirt1/PGC-1α pathway, oxidation and antioxidant balance, and lipid metabolism in aging muscle.


Asunto(s)
Proteínas de Drosophila , Condicionamiento Físico Animal , Animales , Masculino , Humanos , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Drosophila/metabolismo , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Terapia por Ejercicio , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
2.
Diabetes Obes Metab ; 26(7): 2673-2683, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38558498

RESUMEN

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etiología , Reino Unido/epidemiología , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Adulto , Factores de Riesgo , Índice de Masa Corporal , Fumar/efectos adversos , Fumar/epidemiología , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Ejercicio Físico , Estudios de Seguimiento , Presión Sanguínea , Incidencia
3.
Arterioscler Thromb Vasc Biol ; 43(9): 1684-1699, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37409531

RESUMEN

BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.


Asunto(s)
MicroARNs , ARN Largo no Codificante , Calcificación Vascular , Humanos , Ratas , Animales , MicroARNs/metabolismo , Aldosterona/toxicidad , ARN Largo no Codificante/metabolismo , Osteogénesis , Calcificación Vascular/inducido químicamente , Calcificación Vascular/genética , Calcificación Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo
4.
Nutr Metab Cardiovasc Dis ; 34(6): 1407-1415, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38664127

RESUMEN

BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.


Asunto(s)
Aneurisma de la Aorta , Disección Aórtica , Ácido Ascórbico , Factores Protectores , Vitamina E , Humanos , Masculino , Estudios Prospectivos , Persona de Mediana Edad , Femenino , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Vitamina E/administración & dosificación , Factores de Riesgo , Anciano , Incidencia , Disección Aórtica/epidemiología , Disección Aórtica/prevención & control , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/prevención & control , Medición de Riesgo , Reino Unido/epidemiología , Factores de Tiempo , Dieta/efectos adversos , Adulto
5.
Clin Exp Nephrol ; 28(4): 325-336, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38151608

RESUMEN

BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.


Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Estados Unidos , Biobanco del Reino Unido , Bancos de Muestras Biológicas , Estudios Prospectivos , Predisposición Genética a la Enfermedad , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Factores de Riesgo
6.
Arterioscler Thromb Vasc Biol ; 42(5): 677-688, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35387482

RESUMEN

BACKGROUND: To investigate whether obesity with or without metabolic syndrome is prospectively associated with coronary artery calcium (CAC) progression and incident cardiovascular disease events. METHODS: A total of 1730 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults) were included (age, 40.1±3.6 years; 38.3% men), who completed computed tomography of CAC at baseline (year 15: 2000-2001) and follow-up (year 20 or 25). Metabolically healthy obesity (MHO) was defined as body mass index≥30 kg/m2 without any metabolic syndrome components in our main analysis. Sensitivity analyses were conducted for several conditions characterizing 4 metabolic phenotypes. RESULTS: During a mean follow-up of 9.1 years, 439 participants had CAC progression. MHO subjects had a significantly higher risk of CAC progression than their metabolically healthy normal weight counterparts (adjusted hazard ratios [95% CIs] from 1.761 [1.369-2.264] to 2.047 [1.380-3.036]) depending on the definition of MHO adopted. Obesity with unhealthy metabolic profile remained the highest significant risk of CAC progression and cardiovascular disease events whatever the definitions adopted for metabolically unhealthy status. Up to 60% of participants with MHO converted to metabolically unhealthy obesity from year 15 to year 20 or year 25. Further sensitivity analysis showed that MHO throughout carried a similar risk of incident cardiovascular disease events compared with metabolically healthy normal weight throughout. CONCLUSIONS: Different metabolic phenotypes of obesity beginning at a young age exhibit distinct risks of CAC progression and subsequent cardiovascular disease events in later midlife. MHO represents an intermediate phenotype between metabolically low- to high-risk obese individuals. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00005130.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Síndrome Metabólico , Obesidad Metabólica Benigna , Adulto , Índice de Masa Corporal , Calcio , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/epidemiología , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Humanos , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/epidemiología , Obesidad Metabólica Benigna/complicaciones , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/epidemiología , Fenotipo , Factores de Riesgo
7.
Acta Pharmacol Sin ; 44(2): 345-355, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35945313

RESUMEN

Abdominal aortic aneurysm (AAA) is a dangerous vascular disease without any effective drug therapies so far. Emerging evidence suggests the phenotypic differences in perivascular adipose tissue (PVAT) between regions of the aorta are implicated in the development of atherosclerosis evidenced by the abdominal aorta more vulnerable to atherosclerosis than the thoracic aorta in large animals and humans. The prevalence of thoracic aortic aneurysms (TAA) is much less than that of abdominal aortic aneurysms (AAA). In this study we investigated the effect of thoracic PVAT (T-PVAT) transplantation on aortic aneurysm formation and the impact of T-PVAT on vascular smooth muscle cells. Calcium phosphate-induced mouse AAA model was established. T-PVAT (20 mg) was implanted around the abdominal aorta of recipient mice after removal of endogenous abdominal PVAT (A-PVAT) and calcium phosphate treatment. Mice were sacrificed two weeks after the surgery and the maximum external diameter of infrarenal aorta was measured. We found that T-PVAT displayed a more BAT-like phenotype than A-PVAT; transplantation of T-PVAT significantly attenuated calcium phosphate-induced abdominal aortic dilation and elastic degradation as compared to sham control or A-PVAT transplantation. In addition, T-PVAT transplantation largely preserved smooth muscle cell content in the abdominal aortic wall. Co-culture of T-PVAT with vascular smooth muscle cells (VSMCs) significantly inhibited H2O2- or TNFα plus cycloheximide-induced VSMC apoptosis. RNA sequencing analysis showed that T-PVAT was enriched by browning adipocytes and anti-apoptotic secretory proteins. We further verified that the secretome of mature adipocytes isolated from T-PVAT significantly inhibited H2O2- or TNFα plus cycloheximide-induced VSMC apoptosis. Using proteomic and bioinformatic analyses we identified cartilage oligomeric matrix protein (COMP) as a secreted protein significantly increased in T-PVAT. Recombinant COMP protein significantly inhibited VSMC apoptosis. We conclude that T-PVAT exerts anti-apoptosis effect on VSMCs and attenuates AAA formation, which is possibly attributed to the secretome of browning adipocytes.


Asunto(s)
Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta , Aterosclerosis , Humanos , Ratones , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Peróxido de Hidrógeno/metabolismo , Secretoma , Músculo Liso Vascular/metabolismo , Cicloheximida/metabolismo , Proteómica , Tejido Adiposo/metabolismo , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/metabolismo , Aorta Abdominal/cirugía , Aterosclerosis/metabolismo , Adipocitos Marrones , Ratones Endogámicos C57BL
8.
Artículo en Inglés | MEDLINE | ID: mdl-35900652

RESUMEN

PURPOSE: Colchicine, a multipotent anti-inflammatory drug, has been reported to alleviate cardiac remodeling and improve cardiac function after acute myocardial infarction (AMI). However, the underlying mechanism remains incompletely understood. Because neutrophils extracellular traps (NETs) enhance inflammation and participate in myocardial ischemia injury, and colchicine can inhibit NETosis, we thus aimed to determine whether colchicine exerts cardioprotective effects on AMI via suppressing NETs. METHODS: Adult C57BL/6 mice were subjected to permanent ligation of the left anterior descending coronary artery and treated with colchicine (0.1 mg/kg/day) or Cl-amidine (10 mg/kg/day) for 7 or 28 days after AMI. Cardiac function was evaluated by echocardiography, and NETs detected by immunofluorescence. ROS production was detected using 2',7'-dichlorodihydrofluorescein diacetates (DCFH-DA) fluorometry. Intracellular Ca2+ concentration was assessed by a fluorometric ratio technique. RESULTS: We found that colchicine treatment significantly increased mice survival (89.8% in the colchicine group versus 67.9% in control, n = 32 per group; log-rank test, p < 0.05) and improved cardiac function at day 7 (left ventricular ejection fraction (LVEF): 28.0 ± 9.2% versus 12.6 ± 3.9%, n = 8 per group; p < 0.001) and at day 28 (LVEF: 26.2 ± 7.2% versus 14.8 ± 6.7%, n = 8 per group; p < 0.001) post-AMI. In addition, the administration of colchicine inhibited NETs formation and inflammation. Furthermore, colchicine inhibited NETs formation by reducing NOX2/ROS production and Ca2+ influx. Moreover, prevention of NETs formation with Cl-amidine significantly alleviated AMI-induced cardiac remodeling. CONCLUSIONS: Colchicine inhibited NETs and cardiac inflammation, and alleviated cardiac remodeling after acute myocardial infarction.

9.
Br J Sports Med ; 56(15): 854-861, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35288374

RESUMEN

OBJECTIVE: The study aimed to assess the associations of physical activity (PA) trajectories across a 25-year span with coronary artery calcium (CAC) progression, and subsequent risk of cardiovascular disease (CVD) events. METHODS: We included 2497 participants from the Coronary Artery Disease Risk Development in Young Adults study who had computed tomography-assessment of CAC at baseline (year 15: 2000-2001) and follow-up (year 20 or 25) and at least three measures of PA from year 0 to year 25. Long-term PA trajectories were determined by latent class modelling using a validated questionnaire. RESULTS: Among the included participants, 1120 (44.9%) were men, 1418 (56.8%) were white, and the mean (SD) age was 40.4 (3.6) years. We identified three distinct PA trajectories based on PA average levels and change patterns: low (below PA guidelines, n=1332; 53.3%); moderate (meeting and slightly over PA guidelines, n=919; 36.8%) and high (about three times PA guidelines or more, n=246; 9.9%). During a mean (SD) follow-up of 8.9 (2.1) years, 640 (25.6%) participants had CAC progression. Participants in the high PA trajectory group had a higher risk of CAC progression than those in the low PA trajectory group after adjustment for traditional cardiovascular risk factors (HR 1.51; 95% CI 1.18 to 1.94). However, high PA trajectory was not associated with an increased risk of incident CVD events (HR 1.01; 95% CI 0.44 to 2.31) and the incidence of CVD events in participants with CAC progression was similar across all three PA trajectory groups (p=0.736). CONCLUSION: Long-term PA about three times the guidelines or more is independently associated with CAC progression; however, no additional risk of incident CVD events could be detected.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Adulto , Calcio , Enfermedades Cardiovasculares/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Ejercicio Físico , Femenino , Humanos , Masculino , Medición de Riesgo , Factores de Riesgo , Adulto Joven
10.
J Cell Physiol ; 236(6): 4403-4419, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33184863

RESUMEN

Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.


Asunto(s)
Autofagia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Interleucina-33/farmacología , Miocitos Cardíacos/efectos de los fármacos , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Modelos Animales de Enfermedad , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ácido Palmítico/toxicidad , Ratas Sprague-Dawley , Transducción de Señal
11.
Cardiovasc Diabetol ; 20(1): 126, 2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34167539

RESUMEN

BACKGROUND: It remains unclear whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is prospectively associated with incident peripheral arterial disease (PAD). METHODS: We included 12,320 Atherosclerosis Risk in Communities Study participants (aged 54.3 ± 5.7 years) free of a history of PAD at baseline (visit 1: 1987-1989). The TyG index was determined using ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and measured at 5 visits between 1987 and 2013. Incident PAD was defined as the first hospitalization with PAD diagnosis or a new onset of measured ABI < 0.90 during follow-up visits. We quantified the association of both baseline and trajectories of TyG index with incident PAD using Cox regression and logistic regression analysis, respectively. RESULTS: Over a median follow-up of 23 years, 1300 participants developed PAD. After adjustment for traditional PAD risk factors, each 1-SD (0.58) increase in TyG index was associated with an 11.9% higher risk of incident PAD [hazard ratio, 1.119 (95% CI, 1.049-1.195)]. Results were similar when individuals were categorized by TyG index quartiles [hazard ratio, 1.239 (95% CI, 1.028-1.492); comparing extreme quartiles]. Four distinct trajectories of stable TyG indexes at various levels along the follow-up duration were identified [low (22.2%), moderate (43.2%), high (27.5%), and very high (7.1%) trajectory groups]. Compared with those with a TyG index trajectory at a low level, those participants with TyG index trajectories at high and very high levels had an even greater risk of future incident PAD [odds ratio (95%CI): 1.404 (1.132-1.740) and 1.742 (1.294-2.344), respectively] after multivariate adjustments for traditional PAD risk factors. CONCLUSIONS: Higher TyG index is independently associated with an increased risk of incident PAD. Long-term trajectories of TyG index help identify individuals at a higher risk of PAD who deserve specific preventive and therapeutic approaches. TRIAL REGISTRATION: Clinical trial registration number: The ARIC trial was registered at clinicaltrials.gov as NCT00005131.


Asunto(s)
Glucemia/metabolismo , Resistencia a la Insulina , Enfermedad Arterial Periférica/sangre , Triglicéridos/sangre , Biomarcadores/sangre , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/epidemiología , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Estados Unidos/epidemiología
12.
Eur J Nutr ; 60(5): 2759-2767, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33394121

RESUMEN

PURPOSE: Zinc is considered protective against atherosclerosis; however, the association between dietary zinc intake and cardiovascular disease remains debated. We investigated whether dietary zinc intake was associated with coronary artery calcium (CAC) progression in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: This analysis included 5186 participants aged 61.9 ± 10.2 years (48.8% men; 41.3% white, 25.0% black, 21.6% Hispanic, and 12.1% Chinese American) from the MESA. Dietary zinc intake was assessed by a self-administered, 120-item food frequency questionnaire at baseline (2000-2002). Baseline and follow-up CAC were measured by computed tomography. CAC progression was defined as CAC > 0 at follow-up for participants with CAC = 0 at baseline; and an annualized change of 10 or percent change of ≥ 10% for those with 0 < CAC < 100 or CAC ≥ 100 at baseline, respectively. RESULTS: Dietary zinc intake was 8.4 ± 4.5 mg/day and 2537 (48.9%) of the included participants had CAC at baseline. Over a median follow-up of 3.4 years (25th-75th percentiles = 2.0-9.1 years), 2704 (52.1%) participants had CAC progression. In the fully adjusted model, higher dietary zinc was associated with a lower risk of CAC progression in both men (hazard ratio [HR] 0.697, 95% confidence interval [CI] 0.553-0.878; p = 0.002) and women (HR 0.675; 95% CI 0.496-0.919; p = 0.012, both comparing extreme groups). Furthermore, such an inverse association was attributable to dietary zinc intake from non-red meat (p < 0.05), rather than red meat sources (p > 0.05). CONCLUSIONS: In this multiethnic population free of clinically apparent cardiovascular disease, higher dietary zinc intake from non-red meat sources was independently associated with a lower risk of CAC progression. CLINICAL TRIAL REGISTRATION NUMBER: The MESA trial was registered at clinicaltrials.gov as NCT00005487.


Asunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Aterosclerosis/epidemiología , Aterosclerosis/prevención & control , Calcio , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/prevención & control , Vasos Coronarios/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Zinc
13.
J Cell Mol Med ; 24(23): 13648-13659, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33150736

RESUMEN

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)-enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α-SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3-MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate-activated protein kinase (AMPK) by Compound C attenuated Aldo/MR-enhanced VC. These results suggested that Aldo facilitates high Pi-induced VSMC osteogenic phenotypic switch and calcification through MR-mediated signalling pathways that involve AMPK-dependent autophagy, which provided new insights into Aldo excess-associated VC in various settings.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Aldosterona/metabolismo , Autofagia , Fosfatos/metabolismo , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Aldosterona/farmacología , Animales , Autofagia/efectos de los fármacos , Biomarcadores , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Expresión Génica , Genes Reporteros , Ratones , Modelos Biológicos , Osteogénesis/efectos de los fármacos , Fosfatos/farmacología , Transducción de Señal/efectos de los fármacos , Calcificación Vascular/patología
14.
J Transl Med ; 18(1): 68, 2020 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-32046736

RESUMEN

AIM: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury. METHODS: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice. RESULTS: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes. CONCLUSION: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.


Asunto(s)
Tejido Adiposo , Proteína C-Reactiva , Tejido Adiposo/patología , Animales , Humanos , Hiperplasia/patología , Ratones , Ratones Endogámicos C57BL , Neointima/patología
16.
Mar Drugs ; 17(1)2019 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-30609655

RESUMEN

Polysaccharide chromium (III) derivatives are gaining increasing attention in improving type 2 diabetes. In this study, the sulfated polysaccharide from Enteromorpha prolifera (SPE) with 4.8 kDa was prepared by specific enzymatic hydrolysis. The obtained SPE was used to prepare a rhamnan-type sulfated polysaccharide derivative (SPED). Results indicated that O-H, C=O, and S=O were effectively involved in the chelation of SPED (chromium content 20.26%). Acute (half lethal dose > 2.38 g/kg) and sub-acute toxicity showed that SPED had no damaging effects on mice. Anti-diabetic experiment demonstrated that SPED improved glucose metabolism. Moreover, SPED promoted the PI3K/PKB/GSK-3ß signaling pathway by regulating mRNA expression of insulin receptors (IR), insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase kinase 3ß (GSK-3ß). In conclusion, the SPED might represent a novel marine-derived candidate against hyperglycemia, which may undergo further pharmaceutical development as a hypoglycemic agent.


Asunto(s)
Desoxiazúcares/farmacología , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Mananos/farmacología , Polisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hiperglucemia/metabolismo , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
17.
J Transl Med ; 16(1): 105, 2018 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-29669585

RESUMEN

BACKGROUND: Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque. METHODS: We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE-/-) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT. RESULTS: Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses. CONCLUSIONS: Our findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB.


Asunto(s)
Tejido Adiposo/patología , Estrés del Retículo Endoplásmico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Comunicación Paracrina , Placa Aterosclerótica/patología , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/irrigación sanguínea , Tejido Adiposo/trasplante , Tejido Adiposo/ultraestructura , Animales , Aorta/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Masculino , Ratones , FN-kappa B/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Fenilbutiratos/farmacología , Fenilbutiratos/uso terapéutico , Placa Aterosclerótica/tratamiento farmacológico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
18.
Hepatology ; 66(4): 1045-1057, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28407288

RESUMEN

The development of pathogenic mechanisms, specific antiviral treatments and preventive vaccines for hepatitis C virus (HCV) infection has been limited due to lack of cell culture models that can naturally imitate the entire HCV life cycle. Here, we established an HCV cell culture model based on human fetal liver stem cells (hFLSCs) that supports the entire blood-borne hepatitis C virus (bbHCV) life cycle. More than 90% of cells remained infected by various genotypes. bbHCV was efficiently propagated, and progeny virus were infectious to hFLSCs. The virus could be passed efficiently between cells. The viral infectivity was partially blocked by specific antibodies or small interfering RNA against HCV entry factors, whereas HCV replication was inhibited by antiviral drugs. We observed viral particles of approximately 55 nm in diameter in both cell culture media and infected cells after bbHCV infection. CONCLUSION: Our data show that the entire bbHCV life cycle could be naturally imitated in hFLSCs. This model is expected to provide a powerful tool for exploring the process and the mechanism of bbHCV infection at the cellular level and for evaluating the treatment and preventive strategies of bbHCV infection. (Hepatology 2017;66:1045-1057).


Asunto(s)
Células Madre Fetales , Hepacivirus/fisiología , Hígado/citología , Modelos Biológicos , Replicación Viral , Humanos , Hígado/virología , Cultivo Primario de Células , Proteínas Virales/biosíntesis , Liberación del Virus
19.
J Biol Chem ; 291(37): 19532-44, 2016 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-27458015

RESUMEN

High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.


Asunto(s)
Quimiocina CCL2/metabolismo , Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Lipoproteínas HDL/metabolismo , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptores CCR2/metabolismo , Apolipoproteína A-I/metabolismo , Enfermedad de la Arteria Coronaria/patología , Activación Enzimática , Femenino , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Masculino
20.
Biochem Biophys Res Commun ; 487(3): 552-559, 2017 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-28427943

RESUMEN

Increased evidence has showed that normal high density lipoprotein (HDL) could convert to dysfunctional HDL in diseases states including coronary artery disease (CAD), which regulated vascular endothelial cell function differently. Long non-coding RNAs (lncRNAs) play an extensive role in various important biological processes including endothelial cell function. However, whether lncRNAs are involved in the regulation of HDL metabolism and HDL-induced changes of vascular endothelial function remains unclear. Cultured human umbilical vein endothelial cells (HUVECs) were treated with HDL from healthy subjects and patients with CAD and hypercholesterolemia for 24 h, then the cells were collected for lncRNA-Seq and the expressions of lncRNAs, genes and mRNAs were identified. The bioinformatic analysis was used to evaluate the relationship among lncRNAs, encoding genes and miRNAs. HDL from healthy subjects and patients with CAD and hypercholesterolemia leaded to different expressions of lncRNAs, genes and mRNAs, and further analysis suggested that the differentially expressed lncRNAs played an important role in the regulation of vascular endothelial function. Thus, HDL from patients with CAD and hypercholesterolemia could cause abnormal expression of lncRNAs in vascular endothelial cells to affect vascular function.


Asunto(s)
Enfermedad de la Arteria Coronaria/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Lipoproteínas HDL/metabolismo , ARN Largo no Codificante/genética , Células Cultivadas , Femenino , Humanos , Lipoproteínas HDL/administración & dosificación , Masculino , Persona de Mediana Edad , ARN Largo no Codificante/metabolismo
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