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1.
Proc Natl Acad Sci U S A ; 117(30): 17820-17831, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661174

RESUMO

The discovery of atrial secretory granules and the natriuretic peptides stored in them identified the atrium as an endocrine organ. Although neither atrial nor brain natriuretic peptide (ANP, BNP) is amidated, the major membrane protein in atrial granules is peptidylglycine α-amidating monooxygenase (PAM), an enzyme essential for amidated peptide biosynthesis. Mice lacking cardiomyocyte PAM (Pam Myh6-cKO/cKO) are viable, but a gene dosage-dependent drop in atrial ANP and BNP content occurred. Ultrastructural analysis of adult Pam Myh6-cKO/cKO atria revealed a 13-fold drop in the number of secretory granules. When primary cultures of Pam 0-Cre-cKO/cKO atrial myocytes (no Cre recombinase, PAM floxed) were transduced with Cre-GFP lentivirus, PAM protein levels dropped, followed by a decline in ANP precursor (proANP) levels. Expression of exogenous PAM in Pam Myh6-cKO/cKO atrial myocytes produced a dose-dependent rescue of proANP content; strikingly, this response did not require the monooxygenase activity of PAM. Unlike many prohormones, atrial proANP is stored intact. A threefold increase in the basal rate of proANP secretion by Pam Myh6-cKO/cKO myocytes was a major contributor to its reduced levels. While proANP secretion was increased following treatment of control cultures with drugs that block the activation of Golgi-localized Arf proteins and COPI vesicle formation, proANP secretion by Pam Myh6-cKO/cKO myocytes was unaffected. In cells lacking secretory granules, expression of exogenous PAM led to the accumulation of fluorescently tagged proANP in the cis-Golgi region. Our data indicate that COPI vesicle-mediated recycling of PAM from the cis-Golgi to the endoplasmic reticulum plays an essential role in the biogenesis of proANP containing atrial granules.


Assuntos
Amidina-Liases/metabolismo , Grânulos Citoplasmáticos/metabolismo , Átrios do Coração/metabolismo , Oxigenases de Função Mista/metabolismo , Vesículas Secretórias/metabolismo , Amidina-Liases/genética , Animais , Fator Natriurético Atrial/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Expressão Gênica , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos , Camundongos Knockout , Oxigenases de Função Mista/genética , Monócitos/metabolismo , Células Musculares/metabolismo , Vesículas Secretórias/ultraestrutura
2.
Nat Rev Cardiol ; 17(11): 698-717, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32444692

RESUMO

Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.


Assuntos
Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Animais , Apêndice Atrial/citologia , Fibrilação Atrial/metabolismo , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/fisiologia , Remodelamento Atrial , Biomarcadores/metabolismo , GMP Cíclico/metabolismo , Diabetes Mellitus/metabolismo , Fibrose , Regulação da Expressão Gênica no Desenvolvimento , Átrios do Coração/citologia , Humanos , Hipertensão/metabolismo , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/metabolismo , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/fisiologia , Obesidade/metabolismo , Fragmentos de Peptídeos/metabolismo , Prognóstico , Processamento de Proteína Pós-Traducional , Hipertensão Arterial Pulmonar/metabolismo , Vesículas Secretórias/metabolismo , Remodelação Ventricular , Equilíbrio Hidroeletrolítico/fisiologia
3.
Int J Sports Med ; 41(7): 427-442, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32252102

RESUMO

Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into "beige cells" that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.


Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Exercício Físico/fisiologia , Termogênese , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Biomarcadores/metabolismo , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Peptídeo Natriurético Encefálico/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína Desacopladora 1/metabolismo
4.
Metabolism ; 106: 154191, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112822

RESUMO

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in fatty acid metabolism and glucose homeostasis. In the context of dyslipemia, LRP1 is upregulated in the heart. Our aim was to evaluate the impact of cardiomyocyte LRP1 deficiency on high fat diet (HFD)-induced cardiac and metabolic alterations, and to explore the potential mechanisms involved. METHODS: We used TnT-iCre transgenic mice with thoroughly tested suitability to delete genes exclusively in cardiomyocytes to generate an experimental mouse model with conditional Lrp1 deficiency in cardiomyocytes (TNT-iCre+-LRP1flox/flox). FINDINGS: Mice with Lrp1-deficient cardiomyocytes (cm-Lrp1-/-) have a normal cardiac function combined with a favorable metabolic phenotype against HFD-induced glucose intolerance and obesity. Glucose intolerance protection was linked to higher hepatic fatty acid oxidation (FAO), lower liver steatosis and increased whole-body energy expenditure. Proteomic studies of the heart revealed decreased levels of cardiac pro-atrial natriuretic peptide (pro-ANP), which was parallel to higher ANP circulating levels. cm-Lrp1-/- mice showed ANP signaling activation that was linked to increased fatty acid (FA) uptake and increased AMPK/ ACC phosphorylation in the liver. Natriuretic peptide receptor A (NPR-A) antagonist completely abolished ANP signaling and metabolic protection in cm-Lrp1-/- mice. CONCLUSIONS: These results indicate that an ANP-dependent axis controlled by cardiac LRP1 levels modulates AMPK activity in the liver, energy homeostasis and whole-body metabolism.


Assuntos
Resistência à Insulina/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Miócitos Cardíacos/metabolismo , Obesidade/genética , Adenilato Quinase/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Metabolismo dos Lipídeos/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Obesidade/metabolismo , Obesidade/patologia
5.
Oxid Med Cell Longev ; 2020: 7147498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082481

RESUMO

Musa balbisiana Colla (Family: Musaceae), commonly known as banana and native to India and other parts of Asia, is very rich in nutritional value and has strong antioxidant potential. In the present study, we have developed Musa balbisiana (MB) fruit pulp powder and evaluated its cardioprotective effect in cardiac hypertrophy, which is often associated with inflammation and oxidative stress. An ultra-high-pressure liquid chromatography-mass spectrometer (UPLC-MS/MS) has been used for the detection and systematic characterization of the phenolic compounds present in Musa balbisiana fruit pulp. The cardioprotective effect of MB was evaluated in a rat model of isoproterenol- (ISO-) induced cardiac hypertrophy by subcutaneous administration of isoproterenol (5 mg/kg-1/day-1), delivered through an alzet minipump for 14 days. Oral administration of MB fruit pulp powder (200 mg/kg/day) significantly (p < 0.001) decreased heart weight/tail length ratio and cardiac hypertrophy markers like ANP, BNP, ß-MHC, and collagen-1 gene expression. MB also attenuated ISO-induced cardiac inflammation and oxidative stress. The in vivo data were further confirmed in vitro in H9c2 cells where the antihypertrophic and anti-inflammatory effect of the aqueous extract of MB was observed in the presence of ISO and lipopolysaccharide (LPS), respectively. This study strongly suggests that supplementation of dried Musa balbisiana fruit powder can be useful for the prevention of cardiac hypertrophy via the inhibition of inflammation and oxidative stress.


Assuntos
Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Frutas/metabolismo , Inflamação/metabolismo , Musa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Linhagem Celular , Cromatografia Líquida , Colágeno/genética , Colágeno/metabolismo , Frutas/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Inflamação/complicações , Inflamação/tratamento farmacológico , Isoproterenol/administração & dosagem , Isoproterenol/toxicidade , Lipopolissacarídeos/farmacologia , Masculino , Musa/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/metabolismo , Polifenóis/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Miosinas Ventriculares/metabolismo
6.
Int Heart J ; 61(1): 77-82, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31956150

RESUMO

This study aimed to evaluate whether the heart is the target organ of endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with heart failure (HF) with reduced ejection fraction (HFrEF).We measured the plasma levels of cyclic guanosine monophosphate (cGMP), which is a second messenger of ANP and BNP, in the aortic root (AO) and coronary sinus (CS) in 237 patients with HFrEF. Plasma levels of cGMP were significantly higher in the CS than those in the AO in 237 patients with HFrEF (10.0 ± 4.5 versus 10.5 ± 4.3 pmoL/mL, P < 0.0001) and were significantly higher in the CS than those in the AO (8.0 ± 3.6 versus 8.9 ± 3.8 pmoL/mL, P < 0.0001) in mild HF patients (New York Heart Association (NYHA) II, n = 114), but there was no difference in plasma cGMP between the AO and the CS (11.9 ± 4.4 versus 11.9 ± 4.3 pmoL/mL, NS) in severe HF patients (NYHA III-IV, n = 123). In mild HF patients, log (ANP + BNP) in the AO was an independent predictor of (CS-AO) cGMP among hemodynamics and nitrate therapy. There was a significant correlation between log [(CS-AO) ANP + (CS-AO) BNP] and (CS-AO) cGMP (r = 0.455, P < 0.0001) in mild HF patients.These findings indicate that cGMP is produced from the failing heart and that the heart is the target organ of endogenous ANP and BNP in patients with HFrEF. In severe HF patients, cGMP production may be attenuated because of the downregulation of biological receptors and/or increased cGMP degradation in the failing heart.


Assuntos
Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/fisiopatologia , Peptídeo Natriurético Encefálico/metabolismo , Idoso , Cateterismo Cardíaco , GMP Cíclico/sangue , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico
7.
Mol Med Rep ; 21(2): 806-814, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974621

RESUMO

Angiotensin II (Ang II) is an important bioactive peptide in the renin­angiotensin system, and it can contribute to cell proliferation and cardiac hypertrophy. Dysfunctions in transient receptor potential canonical (TRPC) channels are involved in many types of cardiovascular diseases. The aim of the present study was to investigate the role of the TRPC channel inhibitor SKF­96365 in cardiomyocyte hypertrophy induced by Ang II and the potential mechanisms of SKF­96365. H9c2 cells were treated with different concentrations of Ang II. The expression levels of cardiomyocyte hypertrophy markers and TRPC channel­related proteins were also determined. The morphology and surface area of the H9c2 cells, the expression of hypertrophic markers and TRPC channel­related proteins and the [3H] leucine incorporation rate were detected in the Ang II­treated H9c2 cells following treatment with the TRPC channel inhibitor SKF­96365. The intracellular Ca2+ concentration was tested by flow cytometry. The present results suggested that the surface area of H9c2 cells treated with Ang II was significantly increased compared with untreated H9c2 cells. The fluorescence intensity of α­actinin, the expression of hypertrophic markers and TRPC­related proteins, the [3H] leucine incorporation rate and the intracellular Ca2+ concentration were all markedly increased in the Ang II­treated H9c2 cells but decreased following SKF­96365 treatment. The present results suggested that Ang II induced cardiomyocyte hypertrophy in H9c2 cells and that the TRPC pathway may be involved in this process. Therefore, SKF­96365 can inhibit cardiomyocyte hypertrophy induced by Ang II by suppressing the TRPC pathway. The present results indicated that TRPC may be a therapeutic target for the development of novel drugs to treat cardiac hypertrophy.


Assuntos
Imidazóis/farmacologia , Miócitos Cardíacos/patologia , Actinina/genética , Actinina/metabolismo , Angiotensina II , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Forma Celular/efeitos dos fármacos , Fluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertrofia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo
8.
Cardiovasc Pathol ; 44: 107160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31759320

RESUMO

Chromogranin B and inositol 1,4,5-trisphosphate-associated calcium signaling leading to increased natriuretic peptide production has been described in cardiac hypertrophy. Here, we performed left anterior descending coronary artery ligation in rats as a model for systolic heart failure and examined protein and gene expression clusters in the infarcted and noninfarcted myocardium and moreover under treatment with metoprolol. We found that atrial natriuretic peptide gene transcription was significantly more elevated in the infarcted compared with the noninfarcted myocardium. Chromogranin B, which facilitates calcium release from internal stores through the inositol 1,4,5-trisphosphate receptor, was upregulated in both areas. Interestingly, angiotensin II receptor type 1 gene transcription was significantly upregulated in the infarcted and unchanged in the noninfarcted myocardium. Nuclear factor ĸappa B as a calcium-dependent transcription factor showed increased activity in the infarction zone. The ß-adrenergic axis does not seem to be involved, as metoprolol treatment did not have a significant impact on any of these results. We conclude that region-specific upregulation of angiotensin II receptor type 1 is a major factor for increased atrial natriuretic peptide production in the infarcted anterior wall. This effect is most likely achieved through inositol 1,4,5-trisphosphate-mediated cytosolic calcium increase and subsequent nuclear factor ĸappa B activation, which is a known transcription factor for natriuretic peptides.


Assuntos
Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Fator Natriurético Atrial/genética , Sinalização do Cálcio , Cromogranina B/genética , Cromogranina B/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Metoprolol/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , NF-kappa B/metabolismo , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/genética
9.
Cardiovasc Pathol ; 45: 107181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31865268

RESUMO

The present study aimed to evaluate the effects of diabetes on quantitative parameters of right atrial cardiomyocytes of elderly rats. Wistar rats (14 months of age) were divided into two groups: streptozotocin-diabetic rats (DG) and control rats (CG). The groups were sacrificed at 16 months. Ultrafine sections of the right atrium were analyzed by electron microscopy. In elderly diabetic animals, histograms of the frequency distribution of natriuretic peptides according to their size showed increased number of small and medium peptides in relation to large peptides, which increased its numerical density leading to a decrease in the mean diameter of both natriuretic peptides. However, elderly diabetic animals remained normotensive. No significant difference was observed between the groups for the volume density of mitochondria, endoplasmic reticulum, and Golgi apparatus. In conclusion, elderly diabetic rats showed increased functional activity of atrial cardiomyocytes with greater production of natriuretic peptides in association with a quantitative maintenance of cytoplasmic components.


Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/patologia , Átrios do Coração/ultraestrutura , Miócitos Cardíacos/ultraestrutura , Fatores Etários , Animais , Fator Natriurético Atrial/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Átrios do Coração/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Ratos Wistar , Estreptozocina , Regulação para Cima
10.
Cell Physiol Biochem ; 53(6): 961-981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820856

RESUMO

BACKGROUND/AIMS: We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. METHODS: Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. RESULTS: Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. CONCLUSION: Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticagrelor/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Endoglina/genética , Endoglina/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/farmacologia , Cloridrato de Prasugrel/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Ticagrelor/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
11.
Andrologia ; 51(10): e13387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31661170

RESUMO

Natriuretic peptide (NP) family is composed of atrial, brain and C-type NP (NPPA, NPPB and NPPC). Here, we aimed to investigate NP expression in testis and epididymis during postnatal development. NPPA expression was observed in gonocytes at prepubertal period but in only spermatocytes in pachytene and leptotene/zygotene stage at pubertal period. In prepubertal and pubertal periods, we detected NPPB expression in only Leydig cells. However, NPPC expression was detected in all of the gonocytes and Sertoli cells, spermatocytes and some interstitial cells in prepubertal and pubertal periods. In postpubertal and mature periods, NPPA and NPPB staining were detected in Leydig cells, elongated and round spermatids but not in spermatogonia and spermatocytes. However, we observed NPPC expression in all cells of the seminiferous tubules and Leydig cells in the postpubertal and mature periods. Epididymal epithelium showed intense NPPC expression during postnatal period but weak NPPA and NPPB expression in prepubertal and pubertal periods. The expression of three NPs in the testis significantly increased after puberty. In conclusion, puberty had a significant effect on NP expression in testis. Unlike NPPA and NPPB, expression of NPPC in all cells of the seminiferous tubule suggests that NPPC is effective in each step of spermatogenesis.


Assuntos
Epididimo/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Maturidade Sexual , Espermatogênese , Testículo/metabolismo , Animais , Fator Natriurético Atrial/análise , Fator Natriurético Atrial/metabolismo , Epididimo/crescimento & desenvolvimento , Masculino , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Tipo C/análise , Ratos , Análise Espaço-Temporal , Testículo/crescimento & desenvolvimento
12.
Cell Physiol Biochem ; 53(4): 587-605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535830

RESUMO

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.


Assuntos
Rim/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervoso Simpático/metabolismo , Animais , Atenolol/farmacologia , Atenolol/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacologia , Enalapril/uso terapêutico , Interleucina-6/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo
13.
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
14.
PLoS Comput Biol ; 15(9): e1007346, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513566

RESUMO

We performed a mathematical analysis of the dynamic control loops regulating the vasomotor tone of vascular smooth muscle, blood volume, and mean arterial pressure, which involve the arginine vasopressin (AVP) system, the atrial natriuretic peptide system (ANP), and the renin-angiotensin-aldosterone system (RAAS). Our loop analysis of the AVP-ANP-RAAS system revealed the concurrent presence of two different regulatory mechanisms, which perform the same qualitative function: one affects blood pressure by regulating vasoconstriction, the other by regulating blood volume. Both the systems are candidate oscillators consisting of the negative-feedback loop of a monotone system: they admit a single equilibrium that can either be stable or give rise to oscillatory instability. Also a subsystem, which includes ANP and AVP stimulation of vascular smooth muscle cells, turns out to be a candidate oscillator composed of a monotone system with multiple negative feedback loops, and we show that its oscillatory potential is higher when the delays along all feedback loops are comparable. Our results give insight into the physiological mechanisms ruling long-term homeostasis of blood hydraulic parameters, which operate based on dynamical loops of interactions.


Assuntos
Pressão Sanguínea/fisiologia , Volume Sanguíneo/fisiologia , Homeostase/fisiologia , Modelos Biológicos , Arginina Vasopressina/metabolismo , Fator Natriurético Atrial/metabolismo , Cálcio/metabolismo , Biologia Computacional , Retroalimentação Fisiológica/fisiologia , Humanos , Músculo Liso Vascular/citologia , Sistema Renina-Angiotensina/fisiologia
15.
Eur J Pharmacol ; 861: 172620, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437429

RESUMO

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Fator Natriurético Atrial/metabolismo , Moléculas de Adesão Celular/metabolismo , Quimiocina CXCL12/metabolismo , AMP Cíclico/metabolismo , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glutationa/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptores CXCR4/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
J Toxicol Sci ; 44(7): 505-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270306

RESUMO

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 µg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, ß-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiotoxicidade , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Lactação/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Administração Oral , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Poluentes Ambientais/administração & dosagem , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Animais , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Dibenzodioxinas Policloradas/administração & dosagem , Gravidez
18.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269783

RESUMO

Atrial natriuretic peptide (ANP) is a cardiac hormone with pleiotropic cardiovascular and metabolic properties including vasodilation, natriuresis and suppression of the renin-angiotensin-aldosterone system. Moreover, ANP induces lipolysis, lipid oxidation, adipocyte browning and ameliorates insulin sensitivity. Studies on ANP genetic variants revealed that subjects with higher ANP plasma levels have lower cardio-metabolic risk. In vivo and in humans, augmenting the ANP pathway has been shown to exert cardiovascular therapeutic actions while ameliorating the metabolic profile. MANP is a novel designer ANP-based peptide with greater and more sustained biological actions than ANP in animal models. Recent studies also demonstrated that MANP lowers blood pressure and inhibits aldosterone in hypertensive subjects whereas cardiometabolic properties of MANP are currently tested in an on-going clinical study in hypertension and metabolic syndrome. Evidence from in vitro, in vivo and in human studies support the concept that ANP and related pathway represent an optimal target for a comprehensive approach to cardiometabolic disease.


Assuntos
Fator Natriurético Atrial/metabolismo , Fator Natriurético Atrial/uso terapêutico , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/metabolismo , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Variação Genética , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/genética , Terapia de Alvo Molecular
20.
Zoolog Sci ; 36(3): 215-222, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251490

RESUMO

Anurans occupy a wide variety of habitats of diverse salinities, and their osmoregulatory ability is strongly regulated by hormones. In this study, we compared the adaptability and hormonal responses to osmotic stress between two kajika frogs, Buergeria japonica (B.j.) and B. buergeri, (B.b.), which inhabit coastal brackish waters (BW) in the Ryukyu Islands and freshwater (FW) in the Honshu, respectively. Both hematocrit and plasma Na+ concentration were significantly higher in B.j. than in B.b. when both were kept in FW. After transfer to one-third seawater (simulating the natural BW environment), which is slightly hypertonic to their body fluids, their body mass decreased and plasma Na concentration increased significantly in both species. After transfer, plasma Na+ concentration increased significantly in both species. We examined the gene expression of two major osmoregulatory hormones, arginine vasotocin (AVT) and atrial natriuretic peptide (ANP), after partial cloning of their cDNAs. ANP mRNA levels were more than 10-fold higher in B.j. than in B.b. in FW, but no significant difference was observed for AVT mRNA levels due to high variability, although the mean value of B.j. was twice that of B.b. Both AVT and ANP mRNA levels increased significantly after transfer to BW in B.b. but not in B.j., probably because of the high levels in FW. These results suggest that B.j. maintains high plasma Na+ concentration and anp gene expression to prepare for the future encounter of the high salinity. The unique preparatory mechanism may allow B.j. wide distribution in oceanic islands.


Assuntos
Anuros/fisiologia , Ecossistema , Águas Salinas/química , Tolerância ao Sal/fisiologia , Animais , Fator Natriurético Atrial/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica/efeitos dos fármacos , Japão , Masculino , Osmorregulação/fisiologia , RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cloreto de Sódio/farmacologia , Vasotocina/metabolismo
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