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1.
High Blood Press Cardiovasc Prev ; 26(6): 501-508, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612431

RESUMO

INTRODUCTION: Early alterations in the cardiovascular system have been described in offspring of hypertensive parents, but with conflicting results. AIM: To evaluate the influence of genetic predisposition to hypertension on left ventricular (LV) geometry and function, 30 normotensive male offspring of hypertensive parents (EH+) and 30 matched offspring of normotensive families (EH-), were studied. METHODS: All subjects underwent office and 24-h ambulatory blood pressure monitoring (ABPM), conventional and Tissue Doppler Echocardiography (TDE), including assessment of myocardial performance index (MPI). RESULTS: EH+ showed an increase in office BP with statistical significance in diastolic BP (84 ± 7 vs 73 ± 6 mmHg; p < 0.05). Relative wall thickness (RWT) was greater in EH+ (0.37 ± 0.05 vs 0.31 ± 0.03; p < 0.05) and significantly related to the EH+ condition at the univariate analysis (p < 0.003), whilst the LV mass index was unchanged (84.3 ± 14 vs 80 ± 17 g/m2; p = NS), suggesting a trend towards concentric remodeling. Systolic and diastolic function, in both ventricles, were superimposable in the two groups. The MPI was higher in EH+ (0.49 ± 0.10 vs 0.45 ± 0.08; p = NS) and significantly correlated to RWT (r = 0.47, p < 0.01). However, at the stepwise multiple regression analysis, only the condition of EH + was independently associated with RWT (p <0.006). RWT, according to ROC curves analysis, predicted the condition of EH+ (cutoff 0.359, specificity 89%, sensitivity 82%). CONCLUSION: Current results provide information about LV myocardial performance in EH+ subjects, related to a LV concentric remodeling and to endothelial dysfunction.


Assuntos
Pressão Sanguínea , Filho de Pais Incapacitados , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Estudos de Casos e Controles , Ecocardiografia Doppler , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Medição de Risco , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
2.
Indian Heart J ; 71(3): 199-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543192

RESUMO

OBJECTIVES: The aim of the study was to evaluate the correlation between left ventricular hypertrophy and the gene polymorphism of angiotensin-converting enzyme (ACE) intron deletion (I/D) and ACE G2350A. METHODS: Information related to the sample size and genotype frequencies was extracted from each study. RESULTS: Our results found that the D allele (p = 0.0180) and DD genotype (p = 0.0110) of ACE I/D had a significant association with increasing the risk of left ventricular hypertrophy, whereas the I allele (p = 0.0180), but not II (p = 0.1660) and ID genotypes (p = 0.1430), was associated with decreasing the risk of left ventricular hypertrophy. On other hand, we found that the A allele (p = 0.0020) and GA genotype of ACE G2350A (p = 0.0070) had the correlation with increasing the risk of left ventricular hypertrophy. CONCLUSIONS: Our meta-analysis reveals that the D allele of ACE I/D and the A allele of ACE G2350A are associated with increasing the risk of left ventricular hypertrophy.


Assuntos
Hipertrofia Ventricular Esquerda/genética , Íntrons , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Humanos , Deleção de Sequência
3.
J Hum Genet ; 64(11): 1117-1125, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451716

RESUMO

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.


Assuntos
Alanina-tRNA Ligase/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Fatores de Alongamento de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Doenças Raras/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , DNA Mitocondrial/genética , Disartria/genética , Disartria/fisiopatologia , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Mutação , Oftalmoplegia/genética , Oftalmoplegia/fisiopatologia , Linhagem , Doenças Raras/diagnóstico por imagem , Doenças Raras/fisiopatologia , Sequenciamento Completo do Exoma
4.
Hypertension ; 74(3): 687-696, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31327268

RESUMO

Metabolic syndrome is a cause of coronary artery disease and type 2 diabetes mellitus. Camk2n1 resides in genomic loci for blood pressure, left ventricle mass, and type 2 diabetes mellitus, and in the spontaneously hypertensive rat model of metabolic syndrome, Camk2n1 expression is cis-regulated in left ventricle and fat and positively correlates with adiposity. Therefore, we knocked out Camk2n1 in spontaneously hypertensive rat to investigate its role in metabolic syndrome. Compared with spontaneously hypertensive rat, Camk2n1-/- rats had reduced cardiorenal CaMKII (Ca2+/calmodulin-dependent kinase II) activity, lower blood pressure, enhanced nitric oxide bioavailability, and reduced left ventricle mass associated with altered hypertrophic networks. Camk2n1 deficiency reduced insulin resistance, visceral fat, and adipogenic capacity through the altered cell cycle and complement pathways, independent of CaMKII. In human visceral fat, CAMK2N1 expression correlated with adiposity and genomic variants that increase CAMK2N1 expression associated with increased risk of coronary artery disease and type 2 diabetes mellitus. Camk2n1 regulates multiple networks that control metabolic syndrome traits and merits further investigation as a therapeutic target in humans.


Assuntos
Proteínas de Transporte/genética , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Síndrome Metabólica/fisiopatologia , Adiposidade/genética , Animais , Proteínas de Ligação ao Cálcio , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Síndrome Metabólica/genética , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Medição de Risco , Sensibilidade e Especificidade
5.
J Hum Genet ; 64(9): 891-898, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31213654

RESUMO

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.


Assuntos
Ecocardiografia , Eletrocardiografia , Doença de Fabry , Hipertrofia Ventricular Esquerda , Mutação , Acidente Vascular Cerebral , alfa-Galactosidase/genética , Idoso , Doença de Fabry/diagnóstico por imagem , Doença de Fabry/enzimologia , Doença de Fabry/genética , Doença de Fabry/fisiopatologia , Feminino , Testes Genéticos , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia
6.
Int Urol Nephrol ; 51(8): 1425-1433, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187426

RESUMO

PURPOSE: Cardiovascular events are the major reasons for mortality in haemodialysis patients. Fibroblast growth factor 23 (FGF23), Klotho protein and G-395A Klotho gene polymorphism have been associated with effects on the cardiovascular system. Our study investigates the interrelationship between Klotho protein gene variations, mineral-bone metabolism and left ventricular hypertrophy in patients undergoing chronic haemodialysis programme. MATERIALS AND METHODS: Patients (n = 142) were genotyped for G-395A Klotho gene. Components of mineral-bone metabolism, classical and non-classical (FGF23, Klotho and vitamin D) as well as echocardiographic examination were determined. Predictive models were designed to determine the significance of Klotho gene variations and mineral-bone metabolism components for left ventricle hypertrophy (LVH). RESULTS: A-allele carriers were longer on haemodialysis (p = 0.033), and had higher phosphorus levels (p = 0.016) while the level of Klotho protein was significantly lower (p = 0.001) compared to non-A-allele carriers. The best gains were achieved upon addition of allele A, and all three new markers; the AUC made significant improvement from 0.596 to 0.806 (p < 0.001), and improved net reclassification for 82.1% (95% CI 42.9-121.3%). CONCLUSIONS: The genetic background of A-allele carriers of the G-395A Klotho gene polymorphism increases the susceptibility patients to haemodialysis. A-allele carriers are at a higher risk for the development of cardiovascular complications. The addition of non-classical to classical mineral metabolism components improves prediction power to LVH.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/genética , Glucuronidase/genética , Hipertrofia Ventricular Esquerda/genética , Polimorfismo Genético , Diálise Renal , Idoso , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Estudos de Coortes , Feminino , Humanos , Hipertrofia Ventricular Esquerda/complicações , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
7.
Med Sci Monit ; 25: 3390-3396, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31064975

RESUMO

BACKGROUND This study aimed to explore the association of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphisms with left ventricular hypertrophy (LVH) in Han and Uighur hypertension-OSAHS (obstructive sleep apnea hypopnea syndrome) patients in China. MATERIAL AND METHODS A total of 162 Han and 72 Uygur patients with hypertension-OSAHS were independently subdivided into an LVH group and a non-LVH (NLVH) group based on the left ventricular mass index. The insertion/deletion polymorphisms of ACE gene were determined by polymerase chain reaction. The association of ACE gene insertion/deletion polymorphisms with LVH was assessed by chi-squared test. Logistic regression analysis was performed to obtain the odds ratios and 95% confidence intervals for the risk of LVH after adjusting for confounding factors. RESULTS In Uighur patients, the distributions of D allele and DD genotype showed significant differences between the LVH group and the NLVH group. The difference of DD genotype remained significant after multivariate adjustment. In contrast, no significant differences were observed in the distributions of D allele and DD genotype between the LVH group and the NLVH group in Han patients. Moreover, moderate-severe OSAHS was an independent risk factor for LVH. CONCLUSIONS D allele and DD genotype of ACE gene are possible genetic markers for the risk of LVH in Uighur but not Han hypertension-OSAHS patients.


Assuntos
Hipertrofia Ventricular Esquerda/genética , Peptidil Dipeptidase A/genética , Apneia Obstrutiva do Sono/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Grupos Étnicos/genética , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Hipertensão/complicações , Hipertensão/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Mutação INDEL/genética , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/fisiologia , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Fatores de Risco , Apneia Obstrutiva do Sono/complicações
8.
Mol Genet Genomic Med ; 7(5): e638, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30929317

RESUMO

BACKGROUND: Cardiac involvement in Danon disease typically manifests as left ventricular hypertrophy (LVH) and ventricular preexcitation. This study aimed to identify patients with Danon disease among patients with LVH and concurrent electrocardiographic preexcitation. METHODS: Electrocardiographic preexcitation was identified in 10 of 197 patients with unexplained LVH in whom genetic testing was performed using next-generation sequencing. RESULTS: Three (3/10, 30%) patients with Danon disease were found in association with different mutations in the gene of lysosome-associated membrane protein 2 (LAMP2). Compared to seven patients without Danon disease, these three patients presented with distinctive clinical phenotypes, including onset at an earlier age (20 ± 2 years vs. 53 ± 9 years, p < 0.001), more neurological involvements (100% vs. 0, p = 0.008), higher electrocardiographic voltages (10 ± 1 mV vs. 5 ± 1 mV, p < 0.001), wider QRS complexes (163 ± 5 ms vs. 115 ± 20 ms, p = 0.006), less common asymmetric hypertrophy (0% vs. 86%, p = 0.033), and more frequent elevation of three serum enzymes (creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Intracellular vacuoles accumulation with deficiencies of LAMP2 protein was found in both cardiac and skeletal myocytes of patients with Danon disease. CONCLUSION: In patients with coexistent LVH and ventricular preexcitation, Danon disease is common with distinctive clinical presentations. Comprehensive assessment of these resemble patients can provide valuable findings for early identification and clinical decision making of patients with Danon disease.


Assuntos
Doença de Depósito de Glicogênio Tipo IIb/patologia , Hipertrofia Ventricular Esquerda/patologia , Fenótipo , Adolescente , Adulto , Células Cultivadas , Eletrocardiografia , Doença de Depósito de Glicogênio Tipo IIb/epidemiologia , Doença de Depósito de Glicogênio Tipo IIb/genética , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/genética , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Pessoa de Meia-Idade , Prevalência
9.
Life Sci ; 225: 39-45, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30917908

RESUMO

AIMS: Renin-angiotensin system modulates cardiac structure independent of blood pressure. The present study aimed at investigating whether single nucleotide polymorphism (SNP) and haplotype of angiotensin converting enzyme 2 (ACE2) could influence blood pressure and the susceptibility to hypertensive left ventricular hypertrophy (LVH). SUBJECTS AND METHODS: A total of 647 patients (347 females and 300 males) with newly diagnosed mild to moderate essential hypertension were enrolled in a blood pressure matched, case-control study. Four ACE2 tagSNPs (rs2074192, rs4646176, rs4646155 and rs2106809) were genotyped and major haplotypes consisting of these four SNPs were reconstructed for all subjects. KEY FINDINGS: In females, minor alleles of ACE2 rs2074192 and rs2106809 respectively conferred a 2.1 and 2.0 fold risk for LVH. ACE2 haplotype TCGT increased the risk for LVH while another haplotype CCGC decreased the risk in females. The covariates-adjusted mean left ventricular mass index was 11% greater in TCGT haplotype carriers than in noncarriers in women. In females, the covariates-adjusted mean systolic blood pressure was 3.4 mm Hg lower in CCGC haplotype carriers than in noncarriers. In males, the covariates-adjusted mean systolic blood pressure was 2.4 mm Hg lower in CCGC haplotype carriers than in noncarriers. SIGNIFICANCE: ACE2 tagSNPs rs2074192 and rs2106809 as well as major haplotypes CCGC and TCGT may serve as novel risk markers for LVH in hypertensive patients.


Assuntos
Marcadores Genéticos , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Biol Sex Differ ; 10(1): 8, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728084

RESUMO

BACKGROUND: Maladaptive remodeling in pressure overload (PO)-induced left ventricular hypertrophy (LVH) may lead to heart failure. Major sex differences have been reported in this process. The steroid hormone 17ß-estradiol, along with its receptors ERα and ERß, is thought to be crucial for sex differences and is expected to be protective, but this may not hold true for males. Increasing evidence demonstrates a major role for microRNAs (miRNAs) in PO-induced LVH. However, little is known about the effects of biological sex and ERß on cardiac miRNA regulation and downstream mitochondrial targets. We aimed at the analysis of proteins involved in mitochondrial metabolism testing the hypothesis that they are the target of sex-specific miRNA regulation. METHODS: We employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4. RESULTS: We found a significant decrease of the mitochondrial proteins primarily in the male overloaded heart compared with the corresponding control group. Following computational analysis to identify miRNAs putatively targeting these proteins, our in vitro experiments employing miRNA mimics demonstrated the presence of functional target sites for miRNAs in the 3'-untranslated region of the messenger RNAs coding for these proteins. Next, we assessed the levels of the functionally validated miRNAs under PO and found that their expression was induced only in the male overloaded heart. In contrast, there was no significant effect on miRNA expression in male mice with deficient ERß. CONCLUSION: We put forward that the male-specific induction of miRNAs and corresponding downregulation of downstream protein targets involved in mitochondrial metabolism may contribute to sex-specific remodeling in PO-induced LVH.


Assuntos
Pressão Sanguínea , MicroRNAs/metabolismo , Proteínas Mitocondriais/genética , Miocárdio/metabolismo , Caracteres Sexuais , Animais , Linhagem Celular , Receptor beta de Estrogênio/genética , Feminino , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
PLoS Genet ; 15(2): e1007977, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789911

RESUMO

Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.


Assuntos
Células Endoteliais/citologia , Valvas Cardíacas/crescimento & desenvolvimento , Hipertrofia Ventricular Esquerda/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Linhagem da Célula , Proliferação de Células , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Valvas Cardíacas/citologia , Valvas Cardíacas/metabolismo , Homeostase , Hipertrofia Ventricular Esquerda/veterinária , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
12.
Circulation ; 139(14): 1725-1740, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30636447

RESUMO

BACKGROUND: Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention. METHODS: Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the role of an evolutionary conserved RNA-binding protein Lin28a in pathological cardiac hypertrophy. Next-generation sequencing, RNA immunoprecipitation, and gene expression analyses were applied to identify the downstream targets of Lin28a. Epistatic analysis, metabolic assays, and flux analysis were further used to characterize the effects of Lin28a and its downstream mediator in cardiomyocyte hypertrophic growth and metabolic remodeling. RESULTS: Cardiac-specific deletion of Lin28a attenuated pressure overload-induced hypertrophic growth, cardiac dysfunction, and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA and increased its transcript level. Increasing Pck2 was sufficient to promote hypertrophic growth similar to that caused by increasing Lin28a, whereas knocking down Pck2 attenuated norepinephrine-induced cardiac hypertrophy. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted the role for Lin28a and Pck2 in promoting cardiac biosynthesis required for cell growth. CONCLUSIONS: Our study demonstrates that Lin28a promotes pathological cardiac hypertrophy and glycolytic reprograming, at least in part, by binding to and stabilizing Pck2 mRNA.


Assuntos
Proliferação de Células , Metabolismo Energético , Hipertrofia Ventricular Esquerda/enzimologia , Mitocôndrias Cardíacas/enzimologia , Miócitos Cardíacos/enzimologia , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Glicólise , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Knockout , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/patologia , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Ligação Proteica , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Ratos Sprague-Dawley , Função Ventricular Esquerda , Remodelação Ventricular
13.
Cardiovasc Diabetol ; 18(1): 13, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696455

RESUMO

BACKGROUND: The diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individuals with diabetes at a later stage. The molecular regulators that drive this process in the diabetic heart are still unknown. METHODS: Real-time (RT) PCR analysis was performed to determine the expression of cardiac specific microRNA-208a in right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery. To determine the time-dependent changes, cardiac tissue were collected from type 2 diabetic mice at different age groups. A western blotting analysis was conducted to determine the expression of contractile proteins α- and ß-myosin heavy chain (MHC) and thyroid hormone receptor-α (TR-α), the negative regulator of ß-MHC. To determine the beneficial effects of therapeutic modulation of miR-208a, high glucose treated adult mouse HL-1 cardiomyocytes were transfected with anti-miR-208a. RESULTS: RT-PCR analysis showed marked upregulation of miR-208a from early stages of diabetes in type 2 diabetic mouse heart, which was associated with a marked increase in the expression of pro-hypertrophic ß-MHC and downregulation of TR-α. Interestingly, upregulation of miR-208a preceded the switch of α-/ß-MHC isoforms and the development of diastolic and systolic dysfunction. We also observed significant upregulation of miR-208a and modulation of miR-208a associated proteins in the type 2 human diabetic heart. Therapeutic inhibition of miR-208a activity in high glucose treated HL-1 cardiomyocytes prevented the activation of ß-MHC and hence the hypertrophic response. CONCLUSION: Our results provide the first evidence that early modulation of miR-208a in the diabetic heart induces alterations in the downstream signaling pathway leading to cardiac remodelling and that therapeutic inhibition of miR-208a may be beneficial in preventing diabetes-induced adverse remodelling of the heart.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , MicroRNAs/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Transdução de Sinais , Fatores de Tempo , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo
14.
ESC Heart Fail ; 6(1): 154-163, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30378291

RESUMO

AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV 1.8 in human hypertrophied myocardium. METHODS AND RESULTS: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of NaV 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 µM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca2+ leak and SR-Ca2+ spark frequency after exposure to both NaV 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel NaV 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of NaV 1.8 reduced augmented INaL , abbreviated the action potential duration, and decreased the SR-Ca2+ leak. The findings of our study suggest that NaV 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.


Assuntos
Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/genética , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/genética , RNA/genética , Potenciais de Ação , Idoso , Western Blotting , Diástole , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Miócitos Cardíacos/patologia , Canal de Sódio Disparado por Voltagem NAV1.8/biossíntese , Técnicas de Patch-Clamp , Reação em Cadeia da Polimerase em Tempo Real , Retículo Sarcoplasmático/metabolismo
15.
J Biol Chem ; 294(7): 2543-2554, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30523159

RESUMO

Myocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues, including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D, increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinase-anchoring protein ß (mAKAPß), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAPß signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAPß signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together, these results highlight the importance of mAKAPß signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAPß as a nodal regulator in the myocyte intracellular signaling network.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Calcineurina/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Proteínas de Ancoragem à Quinase A/genética , Animais , Calcineurina/genética , Linhagem Celular , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Miócitos Cardíacos/patologia , Fosforilação , Ratos
16.
J Clin Invest ; 129(2): 531-545, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422822

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.


Assuntos
Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Lamina Tipo A/biossíntese , Mecanotransdução Celular , Miocárdio/metabolismo , Elementos de Resposta , Transativadores/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Lamina Tipo A/genética , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/genética , Transativadores/genética
17.
Circulation ; 139(4): 533-545, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30586742

RESUMO

BACKGROUND: N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known. METHODS: To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function. RESULTS: We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis. CONCLUSIONS: Our study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.


Assuntos
Adenosina/análogos & derivados , Hipertrofia Ventricular Esquerda/enzimologia , Metiltransferases/metabolismo , Miócitos Cardíacos/enzimologia , Função Ventricular Esquerda , Remodelação Ventricular , Adenosina/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metiltransferases/deficiência , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais
18.
Circ Res ; 124(1): 79-93, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582446

RESUMO

RATIONALE: Endoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating transcription factor 6α), an inducer of genes that enhance protein folding and restore ER proteostasis. Because of increased protein synthesis, it is possible that protein folding and ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes. OBJECTIVE: To examine the activity and function of ATF6 during cardiac hypertrophy. METHODS AND RESULTS: We found that ER stress and ATF6 were activated and ATF6 target genes were induced in mice subjected to an acute model of transverse aortic constriction, or to free-wheel exercise, both of which promote adaptive cardiac myocyte hypertrophy with preserved cardiac function. Cardiac myocyte-specific deletion of Atf6 (ATF6 cKO [conditional knockout]) blunted transverse aortic constriction and exercise-induced cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for ATF6 in compensatory myocyte growth. Transcript profiling and chromatin immunoprecipitation identified RHEB (Ras homologue enriched in brain) as an ATF6 target gene in the heart. RHEB is an activator of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a major inducer of protein synthesis and subsequent cell growth. Both transverse aortic constriction and exercise upregulated RHEB, activated mTORC1, and induced cardiac hypertrophy in wild type mouse hearts but not in ATF6 cKO hearts. Mechanistically, knockdown of ATF6 in neonatal rat ventricular myocytes blocked phenylephrine- and IGF1 (insulin-like growth factor 1)-mediated RHEB induction, mTORC1 activation, and myocyte growth, all of which were restored by ectopic RHEB expression. Moreover, adeno-associated virus 9- RHEB restored cardiac growth to ATF6 cKO mice subjected to transverse aortic constriction. Finally, ATF6 induced RHEB in response to growth factors, but not in response to other activators of ATF6 that do not induce growth, indicating that ATF6 target gene induction is stress specific. CONCLUSIONS: Compensatory cardiac hypertrophy activates ER stress and ATF6, which induces RHEB and activates mTORC1. Thus, ATF6 is a previously unrecognized link between growth stimuli and mTORC1-mediated cardiac growth.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Hipertrofia Ventricular Esquerda/enzimologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miócitos Cardíacos/enzimologia , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Ativação Transcricional , Função Ventricular Esquerda , Remodelação Ventricular , Fator 6 Ativador da Transcrição/deficiência , Fator 6 Ativador da Transcrição/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Retículo Endoplasmático/enzimologia , Estresse do Retículo Endoplasmático , Predisposição Genética para Doença , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Fenótipo , Dobramento de Proteína , Proteostase , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Transdução de Sinais
19.
Cardiovasc Res ; 115(1): 71-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931050

RESUMO

Aims: Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results: Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions: Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Insuficiência Cardíaca/terapia , Hipertrofia Ventricular Esquerda/terapia , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/metabolismo , Terapêutica com RNAi , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/metabolismo , Neovascularização Fisiológica , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Transdução de Sinais , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
20.
Probl Radiac Med Radiobiol ; 23: 302-330, 2018 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-30582854

RESUMO

OBJECTIVE: Evaluation of morphological and functional myocardial abnormalities in the Chornobyl NPP (ChNPP)accident clean-up workers (ACUW) of the «iodine¼ period exposed to ionizing radiation at a young age and havinggot the type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The ChNPP ACUW of «iodine¼ period (n=111) exposed to ionizing radiation (IR) at a young age(18-35 years) were involved in the study. Subjects having got the T2DM were included in study Group I (n = 66), per-sons with normal glucose challenge test were selected as a comparison Group II (n = 45). External radiation doses (ERD)ranged from 10 to 860 mSv. The Group III (clinical control) included persons having got the T2DM with no radiationexposure in a history (n=20). Group IV was the normative one. There was no statistical difference between the groups inage, sociodemographic characteristics and level of education. Echocardiography and cardiac Doppler sonography wereperformed in one- and two-dimensional regimens according to the recommendations of the European Association ofEchocardiography. Total adiponectin and proinflammatory cytokine (TNF-α and IL-6) concentrations were assayed by theimmunoenzyme method. Statistical processing of data was carried out using the Microsoft® Exel 2002 software. RESULTS: Myocardial remodeling in the ChNPP ACUW of a «iodine¼ period having the T2DM occurred through a sig-nificant increase of its linear parameters. Volumetric parameters (EDV, ESV and their indexes) were within maximumpermissible limits significantly exceeding however the values in the Group IV. There was aт increase in myocardialmass of the left ventricle and its indices with the formation of structural-geometric abnormalities, mainly in theform of concentric hypertrophy with a decrease in the myocardial contractile capacity. There was no differences ofthe vast majority of key morphometric parameters of myocardium in the dose subgroups, while in persons with ERD> 500 mSv the incidence of serious left ventricular hypertrophy (LVMMI > 149 g/m2) significantly exceeded thisvalue in individuals with lower ERD. At a maximum ERD the more intense fibroplastic processes were observed inmyocardium [a significant increase in the interstitial collagen volumetric fraction (ICVF)] as compared to the caseswith ERD up to 50 mSv. Intensification of myocardial fibroblastic processes occurred in the comparizin group andgroup off clinical control. In combination with concentric myocardial hypertrophy this may lead to an increased riskof cardiovascular complications. Strong negative correlation was revealed between the parameters of left ventricu-lar structure in diastole and adiponectin level in the ChNPP ACUW of a «iodine¼ period with diagnosed T2DM, high-lighting its cardioprotective effect. At the same time, the content of FNP-α and IL-6 proinflammatory cytokines hada positive correlation with the main parameters of abnormal myocardial remodeling, indicating the possibility oftheir role in unfavorable cardiovascular modifications. CONCLUSIONS: The decreased adiponectin level and elevated levels of TNF-α and IL-6 in the ChNPP ACUW of a«iodine¼ period having got the T2DM are the meaningful factors in progression of LV geometric remodeling. Togetherwith fibroplastic processes (a significant increase in ICVF) this may be a basis for the development of myocardialremodeling processes, namely a concentric hypertrophy, which is a prerequisite for the development of complica-tions in cardiovascular system.


Assuntos
Acidente Nuclear de Chernobyl , Diabetes Mellitus Tipo 2/fisiopatologia , Socorristas , Hipertrofia Ventricular Esquerda/fisiopatologia , Exposição Ocupacional/efeitos adversos , Exposição à Radiação/efeitos adversos , Adiponectina/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Ecocardiografia , Expressão Gênica , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/genética , Interleucina-6/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Doses de Radiação , Monitoramento de Radiação/métodos , Radiação Ionizante , Fator de Necrose Tumoral alfa/genética , Ucrânia , Ultrassonografia Doppler
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