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1.
Life Sci ; 242: 117211, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891720

RESUMO

Ventricular hypertrophy is a risk factors for arrhythmias, ischemia and sudden death. It involves cellular modifications leading to a pathological remodeling and is associated with heart failure. The activation of the G protein-coupled estrogen receptor (GPER) mediates beneficial actions in the cardiovascular system. Our goal was to prevent and regress the hypertrophy by the activation of GPER in neonatal cardiac myocytes (NRCM) and SHR male rats. Aldosterone increased the neonatal cardiomyocytes cell surface area after 48 h of incubation. The aldo-induced hypertrophy was blocked by the mineralocorticoid receptor (MR) inhibitor Eplererone or the reduction of MR expression by siRNA. The activation of GPER by the agonist G-1 totally prevented the increase surface area by Ald. The transfection of neonatal rat cardiac myocytes with a siRNA against GPER or the incubation with GPER blockers G-15 and G-36 inhibited the protection of G-1. The significant increase of cell surface area after 48 h of incubation with Ald was totally regressed in 24 h by the presence of G-1, indicating that the activation of GPER not only prevent the hypertrophy but also regress the hypertrophy when it is already established. In the in vivo model, G-1 or Vehicle was constantly infused via the minipump to SHR. The reduction of the hypertrophy by G-1 was evident by the cross-sectional area, BNP and ANP markers and by echocardiography. In this studied we demonstrated that the activation of GPER prevented and regressed the hypertrophy induced by Ald in NRCM and regressed hypertrophy in SHR rats.


Assuntos
Cardiomegalia/prevenção & controle , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Cardiomegalia/diagnóstico por imagem , Células Cultivadas , Ciclopentanos/farmacologia , Ecocardiografia , Eplerenona/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Quinolinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/fisiologia
2.
Environ Pollut ; 255(Pt 1): 113155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539850

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500 µM) and/or TAX (0.5 µM) for 24 h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and ß-myosin heavy cardiac muscle (ß-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1α) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cardiomegalia/prevenção & controle , Dietilexilftalato/toxicidade , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Quercetina/análogos & derivados , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Células Cultivadas , Galinhas/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Quercetina/farmacologia , Miosinas Ventriculares/metabolismo
3.
Biol Pharm Bull ; 42(9): 1471-1481, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474708

RESUMO

Sutaehwan (STH) has been used in Korean medicine for the treatment of abortus habitualis such as fetal restlessness in the uterus. Previously, we reported that a modified formulation of STH, Sutaehwan-Gami, has phytoestrogen-like properties in an ovariectomized menopausal rat model. However, the therapeutic effects of STH and the precise mechanisms by which STH affects various menopausal symptoms remain poorly understood. The current study was designed to explore the effects of a modified form of STH on menopausal anxiety, depression and heart hypertrophy and its mechanisms in 4-vinylcyclohexene diepoxide (VCD)-induced menopausal mouse models. VCD-induced menopausal model mice were fed a modified form of STH, which contained water extract of 3 herbs (called STH_KP17001) at a dose of 100 or 300 mg/kg/d or as a positive control, estradiol at a dose of 0.2 mg/kg/d with standard mouse pellets for 13 weeks. The results show that STH_KP17001 significantly restored the VCD-induced weight reduction of uterine and ovary through the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in the uterus and ovary. Moreover, STH_KP17001 showed slight proliferative effects and estrogen receptor α phosphorylation in MCF-7 cells. Treatment with STH_KP17001 reversed VCD-induced anxiety and depression through AMP-activated protein kinase (AMPK) activation and brain-derived neurotrophic factor (BDNF) expression in the cerebral cortex, while improving heart hypertrophy through inactivation of inhibitor of kappaB α (IκBα) in the heart. The results indicate that STH_KP17001 improves menopause-induced anxiety, depression and heart hypertrophy, implying its protective role for the management of menopausal symptoms.


Assuntos
Ansiedade/prevenção & controle , Cardiomegalia/prevenção & controle , Depressão/prevenção & controle , Menopausa/psicologia , Extratos Vegetais/farmacologia , Animais , Cicloexenos , Modelos Animais de Doenças , Feminino , Humanos , Células MCF-7 , Medicina Tradicional Coreana , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Compostos de Vinila
4.
Life Sci ; 233: 116748, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412263

RESUMO

AIMS: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy. MATERIALS AND METHODS: Male rats were exposed to CIH 8 h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated. KEY FINDINGS: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation. SIGNIFICANCE: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/complicações , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Resveratrol/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Apoptose , Autofagia , Cardiomegalia/etiologia , Cardiomegalia/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
J Mol Histol ; 50(4): 343-354, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111288

RESUMO

Cardiac hypertrophy is a compensatory response in reaction to mechanical load that reduces wall stress by increasing wall thickness. Chronic hypertrophic remodeling involves cardiac dysfunction that will lead to heart failure and ultimately death. Studies have been carried out on cardiac hypertrophy for years, whereas the mechanisms have not been well defined. Tamarixetin (TAM), a natural flavonoid derivative of quercetin, have been demonstrated possessing anti-oxidative and anti-inflammatory effects on multiple diseases. However, little is known about the function of TAM on the development of cardiac hypertrophy. Here, we found TAM could alleviate pressure-overload-induced cardiac hypertrophy in transverse aortic constriction (TAC) mouse model, assessed by ventricular weight/body weight, lung weight/body weight, echocardiographic parameters, as well as myocyte cross-sectional area and the expression of ANP, BNP and Myh7. In vitro, TAM showed a dose dependent inhibitory effect on phenylephrine-induced hypertrophy in H9c2 cardiomyocytes. Furthermore, TAM reversed cardiac remodeling of stress overloaded heart by suppressing apoptosis and the expression of fibrotic-related genes, reduced oxidative stress and ROS production both in vivo and in vitro. In addition, TAM could negatively modulate TAC-induced nuclear translocation of NFAT and the activation of PI3K/AKT signaling pathways. Therefore, these data indicate for the first time that TAM has a protective effect on experimental cardiac hypertrophy and might be a novel candidate for the treatment of cardiac hypertrophy in clinic.


Assuntos
Cardiomegalia/prevenção & controle , Dissacarídeos/farmacologia , Fatores de Transcrição NFATC/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quercetina/análogos & derivados , Animais , Cardiotônicos/farmacologia , Dissacarídeos/uso terapêutico , Fibrose/metabolismo , Camundongos , Fatores de Transcrição NFATC/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
6.
Int Heart J ; 60(3): 728-735, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31105148

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-ß1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of ß-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.


Assuntos
Compostos Benzidrílicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Compostos Benzidrílicos/efeitos adversos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Fibrose/tratamento farmacológico , Glucosídeos/efeitos adversos , Interleucina-6/metabolismo , Cetonas/metabolismo , Masculino , Modelos Animais , Peptídeos Natriuréticos/metabolismo , Ratos , Ratos Endogâmicos Dahl , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
7.
Life Sci ; 225: 29-38, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940538

RESUMO

AIMS: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. MATERIALS AND METHODS: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. KEY FINDINGS: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O2-) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. SIGNIFICANCE: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.


Assuntos
Cardiomegalia/prevenção & controle , Ciclo-Oxigenase 2/química , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Citrato de Sildenafila/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos SHR
8.
Acta Biochim Biophys Sin (Shanghai) ; 51(4): 422-430, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877756

RESUMO

Angiotensin II (AII) has been well known to induce cardiomyocyte hypertrophy. Epigallocatechin-3-gallate (EGCG) is the main active component of green tea and it has been shown to exhibit strong cardioprotective potential, although the underlying molecular mechanisms remain unclear. In this study, we investigated the role and mechanism of EGCG in preventing AII-induced cardiomyocyte hypertrophy using rat H9c2 cardiomyocytes cells. Reactive oxygen species assay, cell size, and mRNA expression of cardiac hypertrophy markers ANP and BNP were assessed in response to AII treatment. In addition, expression of proteins involved in Hippo signaling pathway were determined by western blot analysis. We found that AII treatment resulted in significant upregulation of ANP and BNP expression levels and increase in H9c2 cell size, which were markedly attenuated by EGCG treatment. Furthermore, our results suggested that EGCG inhibited AII-induced cardiac hypertrophy via regulating the Hippo signaling pathway. Therefore, EGCG may be an effective agent for preventing cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Catequina/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Angiotensina II , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Catequina/química , Catequina/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Estrutura Molecular , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
9.
Life Sci ; 222: 88-93, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30822425

RESUMO

AIMS: Cardiac hypertrophy, an independent risk factor for cardiac failure; is associated with oxidative stress. Decline in the proportion of healthy cardiac stem cells (CSCs), possibly mediated by oxidative stress can lead to cardiac failure. The present study was carried out to examine the hypothesis that reduction of oxidative stress restores CSC efficiency and prevents progressive cardiac remodelling. MATERIALS AND METHODS: Six-month old Spontaneously hypertensive rats (SHR) were supplemented with the antioxidant Tempol (20 mg/kg/day) for 14 days. The effect of Tempol on blood pressure and heart were assessed in SHR. Cardiac stem cells were isolated from atrial explants and expanded in culture for assessment of stem cell characteristics. Intracellular reactive oxygen species (ROS), proliferation, migration and senescence were evaluated in cultured atrial CSCs. KEY FINDINGS: Tempol treatment reduced blood pressure, regressed cardiac hypertrophy and reduced oxidative stress in SHR. Compared to Wistar rat, the efficiency of CSCs was significantly compromised in SHR. Tempol reduced intracellular ROS and restored migration potential and proliferative capacity along with reduction of senescent CSCs and expression of senescence proteins p16ink4a and p21. SIGNIFICANCE: Restoration of functional efficiency of CSCs by antioxidants signifies the role of oxidative stress in deterioration of stem cell attributes in the hypertrophic heart. The observations envisage the use of antioxidants as adjuvant medication for maintaining a healthy stem cell population, which can in-turn prevent progressive cardiac remodelling, a major determinant of cardiac failure.


Assuntos
Antioxidantes/uso terapêutico , Cardiomegalia/prevenção & controle , Óxidos N-Cíclicos/uso terapêutico , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Cardiomegalia/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Células Cultivadas , Óxidos N-Cíclicos/farmacologia , Hipertensão/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Marcadores de Spin , Células-Tronco/metabolismo , Resultado do Tratamento
10.
Clin Sci (Lond) ; 133(5): 611-627, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30782608

RESUMO

Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.


Assuntos
Cardiomegalia/metabolismo , Fibronectinas/metabolismo , Miócitos Cardíacos/metabolismo , Remodelação Ventricular , Proteína ADAM10/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Idoso , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Estudos de Casos e Controles , Linhagem Celular , Modelos Animais de Doenças , Feminino , Fibronectinas/genética , Fibrose , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(1): 113-119, 2019 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-30692076

RESUMO

OBJECTIVE: To investigate the inhibitory effect of Zhenwu Decoction on ventricular hypertrophy in rats with uremic cardiomyopathy and explore the mechanism. METHODS: Cardiocytes isolated from suckling rats were divided into control group and indoxyl sulfate (IS) group, and the protein synthesis was assayed with [3H]- leucine incorporation and cellular protein expressions were detected using Western blotting. Fifty SD rats were randomly divided into sham operation group, model group, and low- and high-dose Zhenwu Decoction treatment groups, and except for those in the sham operation group, all the rats underwent 5/6 nephrectomy. Four weeks after the operation, the rats in low- and high-dose treatment groups were given Zhenwu Decoction via gavage at the dose of 4.5 g/kg and 13.5 g/kg, respectively; the rats in the sham-operated and model groups were given an equal volume of distilled water. After 4 weeks of treatment, serum levels of IS were determined, and cardiac and ventricular mass indexes were measured in the rats; cardiac ultrasound was performed and Western blotting was used to measure the expressions of BNP, p-ERK1/2, p-p38 and p-JNK in the myocardium. RESULTS: Rat cardiomyocytes treated with IS showed significantly enhanced protein synthesis and increased expression levels of BNP, p-erk1/2, and p-p38 as compared with the control cells (P < 0.01), but the expression of p-jnk was comparable between the two groups. In the animal experiment, the rats in the model group showed significantly increased serum creatinine (SCr) and urea nitrogen (BUN) levels, 24-h urine protein (24 hUpro), plasma IS level, left ventricular mass index (LVMI) and whole heart mass index (HMI) compared with those in the sham group (P < 0.01); Both LVESD and LVEDD were significantly reduced and LVAWS, LVAWD, LVPWS and LVPWD were significantly increased in the model rat, which also presented with obvious cardiomyocyte hypertrophy and increased myocardial expressions of BNP, p-ERK1/2, p-p38 and p-jnk (P < 0.01). Compared with the rats in the model group, the rats treated with low-dose and high-dose Zhenwu Decoction had significantly lowered levels of SCr, BUN, 24 hUpro and IS (P < 0.05) and decreased LVMI and HMI; LVESD, LVEDD, LVPWS, LVAWS, and LVAWD were improved more obviously in the high-dose group, and the myocardial expressions of BNP, p-ERK1/2, p-p38 and p-JNK was significantly downregulated after the treatment. CONCLUSIONS: Zhenwu Decoctin can reduce plasma IS levels and inhibit ventricular hypertrophy to delay ventricular remodeling in rats with uremic cardiomyopathy.


Assuntos
Cardiomegalia/prevenção & controle , Cardiomiopatias/complicações , Medicamentos de Ervas Chinesas/farmacologia , Ventrículos do Coração , Indicã/sangue , Miócitos Cardíacos/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Indicã/farmacologia , Miócitos Cardíacos/metabolismo , Nefrectomia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
12.
Nutr Metab Cardiovasc Dis ; 29(3): 301-305, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30642787

RESUMO

BACKGROUND AND AIMS: Although many studies have reported the effects of AT1 receptor on dietary salt overload, the role of AT2 receptor in this model is far from completely elucidated. The present study aimed to better understand the role of AT2 receptor in cardiac structure alterations in response to chronic high salt intake in rats. METHODS AND RESULTS: Male Wistar rats were fed a normal or high salt diet from weaning until 18 weeks of age. Both groups were subdivided into two groups. Starting at 7 weeks of age, rats were treated with or without compound 21 (0.3 mg/kg/day, n = 16), an AT2 receptor agonist. Metabolics and structural parameters were measured. BP, transverse cardiomyocyte and intersticial fibrose was higher in animals fed with high salt diet compared with normal salt fed animals. CONCLUSION: Compound 21 prevented the development of cardiac hypertrophy and fibrosis, reduced the increase in blood pressure and prevented the lower weight gain in animals fed a high salt diet.


Assuntos
Cardiomegalia/prevenção & controle , Fármacos Cardiovasculares/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Cloreto de Sódio na Dieta , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Fibrose , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
13.
J Biochem Mol Toxicol ; 33(5): e22283, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623541

RESUMO

Hesperidin (HES), a flavanone glycoside, predominant in citrus fruits, has an agonistic activity on peroxisome proliferator-activated receptor gamma (PPAR-γ). PPAR-γ is an inhibitor of cardiac hypertrophy (CH) signaling pathways. In this study, we investigated the cardioprotective effect of HES in isoproterenol (ISO)-induced CH through PPAR-γ agonistic activity. For this, male albino Wistar rats were divided into six groups (n = 6), that is, normal, ISO-control, HES treatment group (200 mg kg-1 ; p.o.), HES per se (200 mg kg-1 ; p.o.), enalapril treatment group (30 mg kg-1 ; p.o.), and combination group (HES 200 mg kg-1 ; p.o.+enalapril 30 mg kg-1 ; p.o.). ISO (3 mg kg-1 ; s.c.) was administered to all groups except normal and per se to induce CH. HES or enalapril treatment of 28 days significantly attenuated pathological changes, improved cardiac hemodynamics, suppressed oxidative stress, and apoptosis along with an increased PPAR-γ expression. The combination of enalapril with HES exhibited an effect similar to that of HES or enalapril alone on all the aforementioned parameters. Therefore, HES may be further evaluated as a promising molecule for the alleviation of CH.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Cardiotônicos/farmacologia , Hesperidina/farmacologia , PPAR gama/agonistas , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Isoproterenol/efeitos adversos , Isoproterenol/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/biossíntese , Ratos , Ratos Wistar
14.
Biomed Pharmacother ; 110: 155-167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469080

RESUMO

Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical-scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol-1) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti-hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (Ki = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (Ki >1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 µg mL-1 on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders.


Assuntos
Angiotensina II/toxicidade , Produtos Biológicos/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Lactonas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cardiomegalia/metabolismo , Linhagem Celular , Lactonas/química , Lactonas/isolamento & purificação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Octopodiformes , Relação Estrutura-Atividade
15.
Biomed Pharmacother ; 109: 377-385, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30399572

RESUMO

Resiniferatoxin (RTX), a selective transient receptor potential vanilloid 1 (TRPV1) receptor agonist, can eliminate TRPV1+ primary sensory afferents and blunt cardiac sympathetic afferent reflex for a relatively long period. The present study determined the effects of intrathecal RTX administration on transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiac remodeling in rats. Five days before TAC, RTX (2 µg/10 µl) was injected intrathecally into the T2/T3 interspace of rats. Cardiac sympathetic nerve activities (CSNAs) and cardiac structure and function were determined eight weeks after TAC. Intrathecal RTX administration abolished TRPV1 expression in the dorsal horn and reduced over-activated CSNA in the TAC rat model. Hemodynamic analysis revealed that RTX reduced left ventricular end-diastolic pressure, indicating the improvement of cardiac compliance. Histologic analysis, real-time reverse transcription-polymerase chain reaction, and Western blots showed that RTX prevented TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac apoptosis and reduced the expression of apoptotic proteins and myocardial mRNAs. In conclusion, these results demonstrate that focal chemo-ablation of TRPV1+ afferents in the spinal cord protects the heart from pressure overload-induced cardiac remodeling and cardiac dysfunction, which suggest a novel promising therapeutic method for cardiac hypertrophy and diastolic dysfunction.


Assuntos
Técnicas de Ablação/métodos , Cardiomegalia/prevenção & controle , Cardiotônicos/administração & dosagem , Diterpenos/administração & dosagem , Coração/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Coração/inervação , Coração/fisiologia , Injeções Espinhais , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/cirurgia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/fisiologia , Canais de Cátion TRPV/agonistas
16.
FASEB J ; 33(1): 711-721, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30024790

RESUMO

Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD+ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Cardiomegalia/prevenção & controle , Coativador 2 de Receptor Nuclear/fisiologia , Ribonucleotídeos/farmacologia , Função Ventricular Esquerda/fisiologia , Pressão Ventricular , Remodelação Ventricular/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Aminoimidazol Carboxamida/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
17.
Acta Diabetol ; 56(1): 97-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30187136

RESUMO

AIMS: Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling. METHODS: Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry. RESULTS: ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN. CONCLUSIONS: Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.


Assuntos
Cardiomegalia/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Cardiomegalia/etiologia , Cardiomegalia/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/patologia , Losartan/farmacologia , Masculino , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Zucker
18.
Cardiovasc Toxicol ; 19(1): 23-35, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29968071

RESUMO

The present investigation was undertaken to study the effect of silymarin on cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) in Wistar rats. Silymarin was administered for 9 weeks at the end of which we evaluated hypertrophic, hemodynamic, non-specific cardiac markers, oxidative stress parameters, and determined mitochondrial DNA concentration. Hypertrophic control animals exhibited cardiac hypertrophy, altered hemodynamics, oxidative stress, and decreased mitochondrial DNA (mtDNA) concentration. Treatment with silymarin prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Docking studies revealed that silymarin produces maximum docking score with mitogen-activated protein kinases (MAPK) p38 as compared to other relevant proteins docked. Moreover, PAAC-control rats exhibited significantly increased expression of MAPK p38ß mRNA levels which were significantly decreased by the treatment of silymarin. Our data suggest that silymarin produces beneficial effects on cardiac hypertrophy which are likely to be mediated through inhibition of MAPK p38ß.


Assuntos
Cardiomegalia/prevenção & controle , Ventrículos do Coração/efeitos dos fármacos , Silimarina/farmacologia , Animais , Sítios de Ligação , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Proteína Quinase 11 Ativada por Mitógeno/genética , Proteína Quinase 11 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Conformação Proteica , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silimarina/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular
19.
Mol Nutr Food Res ; 63(5): e1800807, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521107

RESUMO

SCOPE: Gallic acid (GA) is a dietary phenolic acid found in tea, red wine, and some plants. It exhibits anti-oxidative and anti-inflammatory activities. Recent studies have revealed that GA has beneficial effects against several cardiovascular diseases; however, whether GA attenuates pressure-overload-induced cardiac hypertrophy and the underlying mechanism remains unclear. METHODS AND RESULTS: Primary cardiomyocyte hypertrophy is stimulated with angiotensin II (Ang II). Cardiac hypertrophic remodeling is induced in mice by transverse aortic constriction (TAC). Myocardial function is evaluated by echocardiographic and hemodynamic analyses, while cardiac tissues are analyzed by histological staining. It is observed that GA significantly decreases Ang II-induced increases in cardiomyocyte size in vitro. Administration of GA in mice markedly improves TAC-induced cardiac dysfunction and attenuates pathological changes, including cardiac myocyte hypertrophy, fibrosis, inflammation, and oxidative stress. Mechanistically, GA inhibits ULK1 and activates autophagy, which induces the degradation of EGFR, gp130, and calcineurin A, thereby inhibiting the downstream signaling cascades (AKT, ERK1/2, JAK2/STAT3, and NFATc1). CONCLUSIONS: The results demonstrate for the first time that GA prevents myocardial hypertrophy and dysfunction via an autophagy-dependent mechanism. Thus, GA represents a promising therapeutic candidate for treating cardiac hypertrophy and heart failure.


Assuntos
Cardiomegalia/prevenção & controle , Ácido Gálico/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Angiotensina II/efeitos adversos , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiotônicos/farmacologia , Crescimento Celular/efeitos dos fármacos , Células Cultivadas , Masculino , Camundongos Endogâmicos C57BL , Miocardite/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
Circulation ; 139(11): 1407-1421, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586752

RESUMO

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças da Aorta/tratamento farmacológico , Arritmias Cardíacas/prevenção & controle , Aterosclerose/tratamento farmacológico , Cardiomegalia/prevenção & controle , Hipertensão/tratamento farmacológico , Propionatos/farmacologia , Angiotensina II , Animais , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/fisiopatologia , Pressão Arterial/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Cardiomegalia/imunologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Hipertensão/fisiopatologia , Masculino , Camundongos Knockout para ApoE , Placa Aterosclerótica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
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