Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 247
Filtrar
1.
Cell Rep ; 24(10): 2757-2772, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30184508

RESUMO

Exercise-induced heart growth provides protection against cardiovascular disease, whereas disease-induced heart growth leads to heart failure. These distinct forms of growth are associated with different molecular profiles (e.g., mRNAs, non-coding RNAs, and proteins), and targeting differentially regulated genes has therapeutic potential for heart failure. The effects of exercise on the cardiac and circulating lipidomes in comparison to disease are unclear. Lipidomic profiling was performed on hearts and plasma of mice subjected to swim endurance training or a cardiac disease model (moderate or severe pressure overload). Several sphingolipid species and phospholipids containing omega-3/6 fatty acids were distinctly altered in heart and/or plasma with exercise versus pressure overload. A subset of lipids was validated in an independent mouse model with heart failure and atrial fibrillation. This study highlights the adaptations that occur to lipid profiles in response to endurance training versus pathology and provides a resource to investigate potential therapeutic targets and biomarkers.


Assuntos
Biomarcadores/sangue , Fosfolipídeos/sangue , Animais , Fibrilação Atrial/sangue , Fibrilação Atrial/metabolismo , Cardiomegalia/sangue , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Humanos , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Fosfolipídeos/metabolismo , Condicionamento Físico Animal , Esfingolipídeos/sangue , Esfingolipídeos/metabolismo
2.
Arterioscler Thromb Vasc Biol ; 38(9): 2028-2040, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29976771

RESUMO

Objective- We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in Scarb1-/- mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in Scarb1-/- mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function. Approach and Results- Transverse aortic constriction (TAC) or sham operation was performed at the age of 14 weeks, 2 weeks after saline injection or after gene transfer with AdSR-BI or with the control vector Adnull. Mortality rate in Scarb1-/- TAC mice was significantly increased compared with wild-type TAC mice during 8 weeks of follow-up (hazard ratio, 2.02; 95% CI, 1.14-3.61). Hepatocyte-specific SR-BI gene transfer performed 2 weeks before induction of pressure overload by TAC potently reduced mortality in Scarb1-/- mice (hazard ratio, 0.329; 95% CI, 0.180-0.600). Hepatocyte-specific SR-BI expression abrogated increased cardiac hypertrophy and lung congestion and counteracted increased myocardial apoptosis and interstitial and perivascular fibrosis in Scarb1-/- TAC mice. Scarb1-/- sham mice were, notwithstanding the absence of detectable structural heart disease, characterized by systolic and diastolic dysfunction and hypotension, which were completely counteracted by AdSR-BI transfer. Furthermore, AdSR-BI transfer abrogated increased end-diastolic pressure and diastolic dysfunction in Scarb1-/- TAC mice. Increased oxidative stress and reduced antioxidant defense systems in Scarb1-/- mice were rescued by AdSR-BI transfer. Conclusions- The detrimental effects of SR-BI deficiency on cardiac structure and function are nullified by hepatocyte-specific SR-BI transfer, which restores HDL metabolism.


Assuntos
Cardiomegalia/terapia , Técnicas de Transferência de Genes , Hepatócitos/metabolismo , Receptores Depuradores Classe B/genética , Animais , Apoptose , Pressão Sanguínea , Cardiomegalia/sangue , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Células Cultivadas , HDL-Colesterol/sangue , Feminino , Fibrose , Expressão Gênica , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo
3.
J Am Heart Assoc ; 7(13)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29929991

RESUMO

BACKGROUND: Adipokines mediate cardiometabolic risk associated with obesity but their role in the pathogenesis of obesity-associated heart failure remains uncertain. We investigated the associations between circulating adipokine concentrations and echocardiographic measures in a community-based sample. METHODS AND RESULTS: We evaluated 3514 Framingham Heart Study participants (mean age 40 years, 53.8% women) who underwent routine echocardiography and had select circulating adipokines measured, ie, leptin, soluble leptin receptor, fatty acid-binding protein 4, retinol-binding protein 4, fetuin-A, and adiponectin. We used multivariable linear regression, adjusting for known correlates (including weight), to relate adipokine concentrations (independent variables) to the following echocardiographic measures (dependent variables): left ventricular mass index, left atrial diameter in end systole, fractional shortening, and E/e'. In multivariable-adjusted analysis, left ventricular mass index was inversely related to circulating leptin and fatty acid-binding protein 4 concentrations but positively related to retinol-binding protein 4 and leptin receptor levels (P≤0.002 for all). Left atrial end-systolic dimension was inversely related to leptin but positively related to retinol-binding protein 4 concentrations (P≤0.0001). E/e' was inversely related to leptin receptor levels (P=0.0002). We observed effect modification by body weight for select associations (leptin receptor and fatty acid-binding protein 4 with left ventricular mass index, and leptin with left atrial diameter in end systole; P<0.05 for interactions). Fractional shortening was not associated with any of the adipokines. No echocardiographic trait was associated with fetuin-A or adiponectin concentrations. CONCLUSIONS: In our cross-sectional study of a large, young to middle-aged, relatively healthy community-based sample, key indices of subclinical cardiac remodeling were associated with higher or lower circulating concentrations of prohypertrophic and antihypertrophic adipokines in a context-specific manner. These observations may offer insights into the pathogenesis of the cardiomyopathy of obesity.


Assuntos
Adipocinas/sangue , Tecido Adiposo/metabolismo , Cardiomegalia/diagnóstico por imagem , Ecocardiografia Doppler , Coração/diagnóstico por imagem , Tecido Adiposo/fisiopatologia , Adiposidade , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/fisiopatologia , Estudos Transversais , Feminino , Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Remodelação Ventricular
4.
Biomed Pharmacother ; 102: 884-893, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710544

RESUMO

The incidence of arrhythmias is the main cause of high mortality after myocardial infarction (AMI). The aim of the present study was to determine whether the rosmarinic acid (RA) could reduce the stretch-induced arrhythmias (SIAs) related to overexpression of NCX1 after AMI. Adult male Sprague-Dawley rats were randomly allocated into six groups: Sham, MI (100 mg/kg of isoproterenol (Iso), subcutaneously, on two consecutive days), RA (30 mg/kg, orally, 14 days), and RA (10, 15 and 30 mg/kg, 14 days) + I. MI induction was performed on the 13th and 14th days of the study period. Forty-eight hours after the first injection of Iso, the parameters of hypertrophy, plasma levels of malondialdehyde (MDA) and lipid profile were evaluated. Using Langendorff apparatus, the isolated hearts were transiently stretched for 5 s with three different end-diastolic volumes (ΔV1to3 = 0.05, 0.1 and 0.2 mL). Cardiac function parameters were measured for 30 s, and ventricular arrhythmias were recorded for 3 min after each stretch. Finally, the levels of cardiac troponin-I and NCX1 mRNA expression were examined. The rats of MI group showed a significant increase in hypertrophy index, MDA, triglyceride and cholesterol (P < 0.001). Additionally, a marked impairment in cardiac parameters, an increase in the rates of SIAs and NCX1 expression, and a decrease in troponin-I (P < 0.001) were observed. RA at three doses especially 15 mg/kg strongly improved almost all the mentioned factors (P < 0.001). Our results confirm that RA pretreatment could prevent hypertrophia, arrhythmia and cardiac dysfunction following AMI which is associated with inhibition of lipid peroxidation and overexpression of NCX1.


Assuntos
Arritmias Cardíacas/complicações , Arritmias Cardíacas/tratamento farmacológico , Cinamatos/uso terapêutico , Depsídeos/uso terapêutico , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Trocador de Sódio e Cálcio/metabolismo , Estresse Mecânico , Animais , Arritmias Cardíacas/sangue , Arritmias Cardíacas/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Cinamatos/farmacologia , Depsídeos/farmacologia , Diástole/efeitos dos fármacos , Eletrocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Masculino , Malondialdeído/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Trocador de Sódio e Cálcio/genética , Taquicardia/sangue , Taquicardia/complicações , Taquicardia/tratamento farmacológico , Taquicardia/fisiopatologia , Triglicerídeos/sangue , Troponina I/metabolismo , Complexos Ventriculares Prematuros/sangue , Complexos Ventriculares Prematuros/complicações , Complexos Ventriculares Prematuros/fisiopatologia
5.
J Cell Physiol ; 233(11): 8850-8861, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29797568

RESUMO

Chronic exercise induces cardiac remodeling that promotes left ventricular hypertrophy and cardiac functional improvement, which are mediated by the mammalian or the mechanistic target of rapamycin (mTOR) as well as by the androgen and glucocorticoid receptors (GRs). However, pathological conditions (i.e., chronic heart failure, hypertension, and aortic stenosis, etc.) also induce cardiac hypertrophy, but with detrimental function, high levels of proinflammatory cytokines and myostatin, elevated fibrosis, reduced adenosine monophosphate-activated protein kinase (AMPK) activation, and fetal gene reactivation. Furthermore, recent studies have evidenced that excessive training induced an inflammatory status in the serum, muscle, hypothalamus, and liver, suggesting a pathological condition that could also be detrimental to cardiac tissue. Here, we verified the effects of three running overtraining (OT) models on the molecular parameters related to physiological and pathological cardiac hypertrophy. C57BL/6 mice performed three different OT protocols and were evaluated for molecular parameters related to physiological and pathological cardiac hypertrophy, including immunoblotting, reverse transcription polymerase chain reaction, histology, and immunohistochemistry analyses. In summary, the three OT protocols induced left ventricle (LV) hypertrophy with signs of cardiac fibrosis and negative morphological adaptations. These maladaptations were accompanied by reductions in AMPKalpha (Thr172) phosphorylation, androgen receptor, and GR expressions, as well as by an increase in interleukin-6 expression. Specifically, the downhill running-based OT model reduced the content of some proteins related to the mTOR signaling pathway and upregulated the ß-isoform of myosin heavy-chain gene expression, presenting signs of LV pathological hypertrophy development.


Assuntos
Cardiomegalia/genética , Hipertrofia Ventricular Esquerda/genética , Inflamação/sangue , Condicionamento Físico Animal/efeitos adversos , Animais , Cardiomegalia/sangue , Cardiomegalia/etiologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Inflamação/etiologia , Inflamação/genética , Inflamação/fisiopatologia , Interleucina-6/genética , Camundongos , Cadeias Pesadas de Miosina/genética , Miosina não Muscular Tipo IIB/genética , Proteínas Quinases/sangue , Proteínas Quinases/genética , Receptores Androgênicos/genética , Receptores de Glucocorticoides/genética
6.
Biomed Res Int ; 2018: 3609645, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29607318

RESUMO

Puromycin aminonucleoside-induced nephrotic syndrome (PAN-NS) is characterized by cardiac remodeling and increased local inflammatory activity. Patients with NS and animal models of NS have vitamin D3 deficiency. The aim of the present study was to evaluate the influence of calcitriol on cardiac remodeling and local inflammatory state in PAN-NS rat model. Male Sprague-Dawley rats were injected with PAN or vehicle on day 0. PAN and control rats were divided into two subgroups for the administration of calcitriol (PAN-D and Ct-D groups) or the vehicle (PAN-V and Ct-V groups) during 21 days. On day 21, the renal function, metabolic balance, calcitriol and FGF-23 plasma levels, prohypertrophy and proinflammatory markers (ET-1, TGF-ß1, TNF-α, and IL-1ß), and calcium signaling molecules (PLB and SERCA-2a) were evaluated. Twenty-one days after injection, PAN-V group presented cardiac hypertrophy and a modulation of proinflammatory markers local expression. Calcitriol treatment of PAN rats prevented cardiac hypertrophy and was associated with marked reduction in the cardiac expression levels of proinflammatory markers. Our results suggest that vitamin D3 deficiency in PAN-NS may contribute to cardiac remodeling and to the increase in local inflammatory activity. Calcitriol treatment prevents both cardiac repercussions and local inflammatory processes in PAN-NS.


Assuntos
Calcitriol/farmacologia , Cardiomegalia , Colecalciferol/deficiência , Citocinas/sangue , Síndrome Nefrótica , Puromicina Aminonucleosídeo/toxicidade , Animais , Cardiomegalia/sangue , Cardiomegalia/etiologia , Cardiomegalia/prevenção & controle , Humanos , Masculino , Síndrome Nefrótica/sangue , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/complicações , Síndrome Nefrótica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
7.
Nutrition ; 51-52: 66-72, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29605766

RESUMO

OBJECTIVES: We aimed to evaluate whether long-term treatment with the soluble non-bacterial fraction of kefir affects mean arterial pressure (MAP) and cardiac hypertrophy through the modulation of baroreflex sensitivity, ACE activity, and the inflammatory-to-anti-inflammatory cytokine ratio in spontaneously hypertensive rats (SHRs). METHODS: SHRs were treated with the soluble non-bacterial kefir fraction (SHR-kefir) or with kefir vehicle (SHR-soluble fraction of milk). Normotensive control Wistar Kyoto animals received the soluble fraction of milk. All treatments were administered by gavage (0.3 mL/100g/body weight), once daily for eight weeks. At the end, after basal MAP and Heart Rate (HT) measurement, barorreflex sensitivity was evaluated through in bolus administrations of sodium nitroprusside and phenylephrine (AP50 [arterial pressure 50%], the lower plateau, and HR range were measured). ACE activity and cytokines (TNF-α and IL-10) were evaluated by ELISA. Cardiac hypertrophy was analysed morphometrically. RESULTS: Compared to SHR control, SHR-kefir exhibited a significant decrease in both MAP (SHR: 184 ± 5; SHR-Kefir: 142 ± 8 mmHg), and HR (SHR: 360 ± 10; SHR-kefir: 310 ± 14 bpm). The non-bacterial fraction of kefir also reduced cardiac hypertrophy, TNF-α-to-IL10 ratio, and ACE activity in SHRs. SHR-kefir baroreflex sensitivity, resulted in a partial but significant recovery of baroreflex gain, as demonstrated by improvements in AP50, the lower plateau, and HR range. CONCLUSION: In summary, our results indicate that long-term administration of the non-bacterial fraction of kefir promotes a significant decrease in both MAP and HR, by improving baroreflex, and reduces cardiac hypertrophy in SHRs, likely via ACE inhibition, and reduction of the TNF-α-to-IL10 ratio.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/sangue , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/dietoterapia , Hipertensão/dietoterapia , Kefir , Animais , Cardiomegalia/sangue , Modelos Animais de Doenças , Frequência Cardíaca , Hipertensão/sangue , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
8.
Clin Sci (Lond) ; 132(11): 1117-1133, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29685981

RESUMO

Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the renin-angiotensin system (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1-7)) has previously been shown to counterbalance pathological effects of angiotensin II (Ang II). The aim of the present study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpresses an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG and wild-type (WT) rats received daily injections (i.p.) of triiodothyronine (T3; 7 µg/100 g of body weight (BW)) or vehicle for 14 days. In contrast with WT rats, the TG rats did not develop cardiac hypertrophy after T3 treatment. Indeed, TG rats displayed reduced systolic blood pressure (SBP) and cardiac hyperdynamic condition induced by hyperthyroidism. Moreover, increased plasma levels of Ang II observed in hyperthyroid WT rats were prevented in TG rats. TG rats were protected from glycogen synthase kinase 3ß (GSK3ß) inactivation and nuclear factor of activated T cells (NFAT) nuclear accumulation induced by T3. In vitro studies evidenced that Ang-(1-7) prevented cardiomyocyte hypertrophy and GSK3ß inactivation induced by T3. Taken together, these data reveal an important cardioprotective action of Ang-(1-7) in experimental model of hyperthyroidism.


Assuntos
Angiotensina I/fisiologia , Cardiomegalia/etiologia , Glicogênio Sintase Quinase 3 beta/fisiologia , Hipertireoidismo/complicações , Fatores de Transcrição NFATC/fisiologia , Fragmentos de Peptídeos/fisiologia , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Cardiomegalia/sangue , Cardiomegalia/diagnóstico por imagem , Células Cultivadas , Ecocardiografia , Hipertireoidismo/sangue , Hipertireoidismo/induzido quimicamente , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Tri-Iodotironina/farmacologia
9.
PLoS One ; 13(3): e0193553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29494668

RESUMO

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.


Assuntos
Estenose Aórtica Supravalvular/dietoterapia , Cardiomegalia/dietoterapia , Gorduras Insaturadas na Dieta/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Estenose Aórtica Supravalvular/sangue , Estenose Aórtica Supravalvular/etiologia , Cardiomegalia/sangue , Cardiomegalia/etiologia , Gorduras Insaturadas na Dieta/farmacologia , Modelos Animais de Doenças , Ácidos Graxos Insaturados/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Espectrometria de Massas , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
10.
Artigo em Inglês | MEDLINE | ID: mdl-29386890

RESUMO

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are caused by a variety of different etiologic agents. Our aim was to phenotype COPD exacerbations using imaging (chest X-ray [CXR] and computed tomography [CT]) and to determine the possible role of the blood tests (C-reactive protein [CRP], the N-terminal prohormone brain natriuretic peptide [NT-proBNP]) as diagnostic biomarkers. Materials and methods: Subjects who were hospitalized with a primary diagnosis of AECOPD and who had had CXRs, CT scans, and blood collection for CRP and NT-proBNP were assessed in this study. Radiologist blinded to the clinical and laboratory characteristics of the subjects interpreted their CXRs and CT images. ANOVA and Spearman's correlation were performed to test for associations between these imaging parameters and the blood-based biomarkers NT-proBNP and CRP; logistic regression models were used to assess the performance of these biomarkers in predicting the radiological parameters. Results: A total of 309 subjects were examined for this study. Subjects had a mean age of 65.6±11.1 years, 66.7% of them were males, and 62.4% were current smokers, with a mean FEV1 54.4%±21.5% of predicted. Blood NT-proBNP concentrations were associated with cardiac enlargement (area under the curve [AUC] =0.72, P<0.001), pulmonary edema (AUC =0.63, P=0.009), and pleural effusion on CXR (AUC =0.64, P=0.01); whereas on CT images, NT-proBNP concentrations were associated with pleural effusion (AUC =0.71, P=0.002). Serum CRP concentrations, on the other hand, were associated with consolidation on CT images (AUC =0.75, P<0.001), ground glass opacities (AUC =0.64, P=0.028), and pleural effusion (AUC =0.72, P<0.001) on CT images. A serum CRP sensitivity-oriented cutoff point of 11.5 mg/L was selected for the presence of consolidation on CT images in subjects admitted as cases of AECOPD, which has a sensitivity of 91% and a specificity of 53% (P<0.001). Conclusion: Elevated CRP may indicate the presence of pneumonia, while elevated NT-proBNP may indicate cardiac dysfunction. These readily available blood-based biomarkers may provide more accurate phenotyping of AECOPD and enable the discovery of more precise therapies.


Assuntos
Proteína C-Reativa/análise , Pulmão/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Área Sob a Curva , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/etiologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Fenótipo , Derrame Pleural/sangue , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Edema Pulmonar/sangue , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/etiologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco
11.
Heart ; 104(13): 1101-1108, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29196542

RESUMO

OBJECTIVE: Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis. METHODS: cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11.3 years. RESULTS: In the mechanism cohort, cMyC concentration correlated with left ventricular mass (adjusted β=11.0 g/m2 per log unit increase in cMyC, P<0.001), fibrosis volume (adjusted β=8.0 g, P<0.001) and extracellular volume (adjusted β=1.3%, P=0.01) in patients with aortic stenosis but not in controls. In those with late gadolinium enhancement (LGE) indicative of myocardial fibrosis, cMyC concentrations were higher (32 (21-56) ng/L vs 17 (12-24) ng/L without LGE, P<0.001). cMyC was unrelated to coronary calcium scores. Unadjusted Cox proportional hazards analysis in the outcome cohort showed greater all-cause mortality (HR 1.49 per unit increase in log cMyC, 95% CI 1.11 to 2.01, P=0.009). CONCLUSIONS: Serum cMyC concentration is associated with myocardial hypertrophy, fibrosis and an increased risk of mortality in aortic stenosis. The quantification of serum sarcomeric protein concentrations provides objective measures of disease severity and their clinical utility to monitor the progression of aortic stenosis merits further study. CLINICAL TRIAL REGISTRATION: NCT1755936; Post-results.


Assuntos
Estenose da Valva Aórtica/sangue , Cardiomegalia/sangue , Proteínas de Transporte/sangue , Miocárdio/patologia , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/patologia , Biomarcadores/sangue , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/mortalidade , Cardiomegalia/patologia , Estudos de Casos e Controles , Morte Celular , Meios de Contraste/administração & dosagem , Feminino , Fibrose , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Remodelação Ventricular
12.
Int J Exp Pathol ; 99(6): 295-303, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30614094

RESUMO

The aim of this study was to establish a robust model of diabetic myocardial hypertrophy in Mus musculus castaneus mice. Mice were fed a high-fat diet for four weeks and then given streptozotocin (STZ, 40 mg kg-1  d-1 for 5 days, intraperitoneally) and fasting blood glucose (FBG) levels were tested after seven days. Mice with FBG levels above 11.1 mmol/L were considered diabetic. Diabetic mice continued to have access to the high-fat diet until cardiac hypertrophy developed. FBG and body weight (BW) were measured weekly. Myocardial hypertrophy was confirmed by left ventricle (LV) hypertrophy index (LVHI), LV/BW, LV histopathological observation and atrial natriuretic factor (ANF) mRNA expression. Serum insulin and plasma haemoglobin A1c (HbA1c) levels, total cholesterol (TCH) and triglyceride (TG) were measured, and then an insulin resistance index (HOMA.IR) was calculated. The level of FBG in the model group remained above 11.1 mmol/L, and the BW showed significant weight loss, compared with the control group (P < 0.01). The high levels of HbA1c, HOME.IR, TCH and TG, and the low level of insulin suggested that glucose metabolism was not balanced with insulin resistance; meanwhile, higher TCH and TG showed that dyslipidaemia had also developed. After the diabetic mice were kept on the high-energy diet for another four  weeks, histopathological observation showed myocardial injuries, much more surface area and collagen fibres, higher LVHI and LV/BW, and elevated expression of ANF mRNA (P < 0.01), suggesting that myocardial hypertrophy had appeared in Mus musculus castaneus mice under the current experimental conditions. Thus a robust model of diabetic myocardial hypertrophy was established four  weeks after confirmation of diabetes, which was induced by feeding a high-fat diet for four weeks combined with a repeated low-dose STZ exposure, in Mus musculus castaneus mice.


Assuntos
Cardiomegalia/etiologia , Diabetes Mellitus Experimental/etiologia , Cardiomiopatias Diabéticas/etiologia , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Cardiomegalia/sangue , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Ventrículos do Coração/patologia , Ventrículos do Coração/ultraestrutura , Resistência à Insulina/fisiologia , Lipídeos/sangue , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Estreptozocina
13.
Cell Physiol Biochem ; 44(6): 2422-2438, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29268252

RESUMO

BACKGROUND: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV) possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. METHODS: The ApoE-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67), senescence (p16INK4a), oxidant (NADPH oxidase 4, NOX4) and antioxidant (superoxide dismutase, SOD) were observed by immunofluorescence staining. RESULTS: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE-/- mice. However, the decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS) in ApoE-/- mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16INK4a in the hearts of ApoE-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. CONCLUSION: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.


Assuntos
Apolipoproteínas E/genética , Cardiomegalia/tratamento farmacológico , Cardiotônicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Cardiomegalia/sangue , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiotônicos/farmacologia , Feminino , Fibrose , Deleção de Genes , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Saponinas/farmacologia , Transcriptoma/efeitos dos fármacos , Triterpenos/farmacologia , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia
14.
J Transl Med ; 15(1): 202, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28985746

RESUMO

BACKGROUND: Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs. METHODS: For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure-volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction. RESULTS: At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure (44.6 ± 5.1 vs 25.9 ± 6.2 mmHg, HYPI vs control, p < 0.05). TTE and ex vivo analyses confirmed severe concentric LV hypertrophy (mean circumferential wall thickness, 19.4 ± 3.1, n = 7 vs 11.4 ± 1.0 mm, n = 5, HYPI vs controls, p < 0.05). The LV and RV mass increased significantly, paralleled by increased isovolumic relaxation constant (tau). Histological analyses confirmed substantial fibrosis and myocyte hypertrophy in both LV and RV. Expressions of ANP, BNP, and miRNA-29a were up-regulated, while SERCA2a and miRNA-1 were down-regulated. Plasma NGAL levels increased gradually, while the elevation of NT-proBNP was detected only at the 5-month FUP. CONCLUSION: These data prove that percutaneous artificial aortic stenosis in pigs is useful for inducing clinically relevant progredient heart failure based on myocardial hypertrophy and fibrosis.


Assuntos
Capilares/patologia , Cardiomegalia/complicações , Cardiomegalia/patologia , Progressão da Doença , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/patologia , Animais , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/fisiopatologia , Biomarcadores/sangue , Capilares/fisiopatologia , Cardiomegalia/sangue , Cardiomegalia/fisiopatologia , Diástole , Modelos Animais de Doenças , Fibrose , Regulação Neoplásica da Expressão Gênica , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Miocárdio/patologia , Pressão , Sus scrofa , Sístole
15.
Int Immunopharmacol ; 48: 102-109, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28499193

RESUMO

Cardiac hypertrophy (CH), as one of the major causes of morbidity and mortality in the world, has become an independent and predictive risk factor for adverse cardiovascular events. However, progress in treatment remains sluggish in recent years. Therefore, compounds derived from non-toxic nature plants are urgently needed. Stachydrine (STA), which is isolated from Leonurus, has various activities, including resistance to cardiovascular disease, but little is known about its effect on CH or the mechanisms. We herein investigated the effect of STA on isoproterenol-induced CH and the underlying mechanisms. Treatment with STA significantly increased the ratios of heart weight/body weight, left ventricle weight/body weight and the cross-sectional areas of cardiomyocytes. In addition, STA significantly decreased the mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide and ß-myosin heavy chain. Furthermore, isoproterenol-induced fibrosis in rats receiving STA was significant attenuated, as evidenced by decreased ratio of fibrotic area/total area and decreased mRNA levels of collagens I and III. Given down-regulation of interleukin-6, tumor necrosis factor-α, interferon-γ (IFN-γ) and IFN-1ß, treatment with STA significantly reversed the expressions of pro-inflammatory induced by isoproterenol. Moreover, STA attenuated the oxidative stress level in serum of isoproterenol-induced CH rats, as shown by increased activity of superoxide dismutase and decreased malondialdehyde level. STA inhibited the expressions of phosphorylated IκBα, NF-κB p65, JAK2 and STAT3 in vivo. Thus, both NF-κB and JAK/STAT signalings played essential roles in mediating the anti-CH effect of STA. Collectively, STA has a potent protective effect on isoproterenol-induced CH, with therapeutic implication for CH.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cardiomegalia , Janus Quinase 2/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Prolina/análogos & derivados , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cardiomegalia/sangue , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Citocinas/sangue , Isoproterenol , Janus Quinase 2/metabolismo , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Prolina/farmacologia , Prolina/uso terapêutico , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Environ Toxicol Pharmacol ; 52: 54-61, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28376377

RESUMO

Combined oral contraceptive (COC) use or inhibition of nitric oxide (NO) synthesis has been shown to cause hypertension and insulin resistance. However, the concomitant effects of COC and NO deficiency on the heart and glucose regulation are not well known. We therefore hypothesized that COC treatment during NO deficiency would lead to the development of cardiac hypertrophy that is associated with aggravated glucose deregulation, pro-inflammatory and pro-fibrotic biomarkers. Eight-week-old female Wistar rats were randomly allotted into control, NO deficient (NG-nitro-l-arginine methyl ester: L-NAME; 20.0mg/kg b.w.), COC-treated (1.0µg ethinylestradiol+5.0µg levonorgestrel, p.o) and L-NAME+COC-treated groups. The animals were treated daily for 6 weeks. Systolic blood pressure was estimated by tail-cuff plethysmography, insulin resistance (IR) and ß-cell function were estimated by homeostatic model of assessment (HOMA-IR and HOMA-ß). Pro-inflammatory (C-reactive protein; CRP and uric acid) and pro-fibrotic (plasminogen activator inhibitor-1; PAI-1) biomarkers were estimated in the plasma. Cardiac histological examination was also done. Results show that COC or L-NAME treatments led to increased blood pressure, HOMA-IR, impaired ß-cell function, PAI-1, CRP and uric acid, without significant effect on cardiac mass. L-NAME+COC-treated group had significantly higher blood pressure, HOMA-IR, impaired ß-cell function, PAI-1, CRP and cardiac mass than COC- or L-NAME-treated groups. Histological examination validated that COC use during NO deficiency causes cardiac hypertrophy. The present study demonstrates that COC treatment and NO deficiency synergistically causes cardiac hypertrophy that is associated with aggravated glucose deregulation, atherogenic dyslipidemia, pro-inflammatory and pro-fibrotic markers.


Assuntos
Cardiomegalia/induzido quimicamente , Anticoncepcionais Orais Combinados/farmacologia , Etinilestradiol/farmacologia , Levanogestrel/farmacologia , Óxido Nítrico/deficiência , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Cardiomegalia/sangue , Estradiol/sangue , Feminino , Resistência à Insulina , NG-Nitroarginina Metil Éster/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Ratos Wistar , Ácido Úrico/sangue
17.
Cardiovasc Res ; 113(6): 598-608, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28453725

RESUMO

Aims: Peripartum cardiomyopathy (PPCM) is a systolic left ventricular dysfunction developing in the peripartum phase in previously healthy women. Relaxin-2 is a pregnancy hormone with potential beneficial effects in heart failure patients. We evaluated Relaxin-2 as a potential diagnostic marker and/or a therapeutic agent in PPCM. Methods and results: In healthy peripartum women, serum Relaxin-2 levels (measured by ELISA in the second half of pregnancy) were elevated showing a decreasing trend in the first postpartum week and returned to non-pregnant levels thereafter. In PPCM patients diagnosed in the first postpartum week, serum Relaxin-2 levels were lower compared to healthy postpartum stage-matched controls. In PPCM patients diagnosed later (0.5-10 months postpartum) Relaxin-2 levels were in the range of non-pregnant controls and not different from healthy postpartum stage-matched controls. In mice, serum Relaxin-1 (functional equivalent of human Relaxin-2) was increased late in pregnancy and rapidly cleared in the first postpartum week. In mice with PPCM due to a cardiomyocyte-specific knockout of STAT3 (CKO) neither low nor high dose of recombinant Relaxin-2 (serelaxin, sRlx-LD: 30 µg/kg/day; sRlx-HD: 300 µg/kg/day) affected cardiac fibrosis, inflammation and heart failure but sRlx-HD increased capillary/cardiomyocyte ratio. sRlx-HD significantly increased heart/body weight ratio and cardiomyocyte cross-sectional area in postpartum CKO and wild-type mice without changing the foetal gene expression program (ANP or ß-MHC). sRlx-HD augmented plasma Prolactin levels in both genotypes, which induced cardiac activation of STAT5. In vitro analyses showed that Prolactin induces cardiomyocyte hypertrophy via activation of STAT5. Conclusion: Although Relaxin-2 levels seemed lower in PPCM patients diagnosed early postpartum, we observed a high pregnancy-related variance of serum Relaxin-2 levels peripartum making it unsuitable as a biomarker for this condition. Supplementation with sRlx may contribute to angiogenesis and compensatory hypertrophy in the diseased heart, but the effects are not sufficient to prevent heart failure in an experimental PPCM model.


Assuntos
Cardiomegalia/patologia , Cardiomiopatias/tratamento farmacológico , Fármacos Cardiovasculares/farmacologia , Insuficiência Cardíaca/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Período Pós-Parto/sangue , Relaxina/farmacologia , Adulto , Animais , Biomarcadores/sangue , Cardiomegalia/sangue , Cardiomegalia/fisiopatologia , Cardiomiopatias/sangue , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Gravidez , Prolactina/sangue , Ratos , Proteínas Recombinantes/farmacologia , Sistema de Registros , Relaxina/sangue , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico , Função Ventricular Esquerda
18.
Am J Pathol ; 187(4): 752-766, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28183531

RESUMO

Arrhythmogenic cardiomyopathy (AC) is a hereditary disease leading to sudden cardiac death or heart failure. AC pathology is characterized by cardiomyocyte loss and replacement fibrosis. Our goal was to determine whether cardiomyocytes respond to AC progression by pathological hypertrophy. To this end, we examined tissue samples from AC patients with end-stage heart failure and tissue samples that were collected at different disease stages from desmoglein 2-mutant mice, a well characterized AC model. We find that cardiomyocyte diameters are significantly increased in right ventricles of AC patients. Increased mRNA expression of the cardiac stress marker natriuretic peptide B is also observed in the right ventricle of AC patients. Elevated myosin heavy chain 7 mRNA expression is detected in left ventricles. In desmoglein 2-mutant mice, cardiomyocyte diameters are normal during the concealed disease phase but increase significantly after acute disease onset on cardiomyocyte death and fibrotic myocardial remodeling. Hypertrophy progresses further during the chronic disease stage. In parallel, mRNA expression of myosin heavy chain 7 and natriuretic peptide B is up-regulated in both ventricles with right ventricular preference. Calcineurin/nuclear factor of activated T cells (Nfat) signaling, which is linked to pathological hypertrophy, is observed during AC progression, as evidenced by Nfatc2 and Nfatc3 mRNA in cardiomyocytes and increased mRNA of the Nfat target regulator of calcineurin 1. Taken together, we demonstrate that pathological hypertrophy occurs in AC and is secondary to cardiomyocyte loss and cardiac remodeling.


Assuntos
Arritmias Cardíacas/complicações , Cardiomegalia/complicações , Cardiomiopatias/complicações , Miócitos Cardíacos/patologia , Animais , Arritmias Cardíacas/sangue , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Sinalização do Cálcio/genética , Cardiomegalia/sangue , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Tamanho Celular , Desmogleína 2/metabolismo , Dilatação , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Insuficiência Cardíaca/patologia , Testes de Função Cardíaca , Ventrículos do Coração/patologia , Humanos , Imunoglobulina G/sangue , Camundongos , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fatores de Transcrição NFATC/metabolismo , Necrose , Tamanho do Órgão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
19.
Am J Pathol ; 187(4): 700-712, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28183533

RESUMO

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.


Assuntos
Hipertensão Pulmonar/etiologia , Embolia Pulmonar/complicações , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Testes de Função Cardíaca , Hemodinâmica/efeitos dos fármacos , Hiperplasia , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Hipóxia/patologia , Hipóxia/fisiopatologia , Indóis/farmacologia , Antígeno Ki-67/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Microesferas , Consumo de Oxigênio/efeitos dos fármacos , Selectina-P/sangue , Pressão Parcial , Condicionamento Físico Animal , Inibidor 1 de Ativador de Plasminogênio/sangue , Poliestirenos , Embolia Pulmonar/sangue , Embolia Pulmonar/fisiopatologia , Pirróis/farmacologia , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Disfunção Ventricular/sangue , Disfunção Ventricular/complicações , Disfunção Ventricular/fisiopatologia
20.
Cardiovasc Res ; 113(2): 134-146, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28082453

RESUMO

AIMS: Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model. METHODS AND RESULTS: We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance. CONCLUSIONS: Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Cardiomiopatias Diabéticas/sangue , Miócitos Cardíacos/metabolismo , Remodelação Ventricular , Fator 3 Ativador da Transcrição/deficiência , Fator 3 Ativador da Transcrição/genética , Animais , Cardiomegalia/sangue , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Diabetes Mellitus Tipo 2/etiologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/farmacologia , Fibrose , Predisposição Genética para Doença , Homeostase , Mediadores da Inflamação/metabolismo , Insulina/sangue , Integrases/genética , Interleucina-6/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Cadeias Pesadas de Miosina/genética , Fenótipo , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/sangue , Remodelação Ventricular/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA