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2.
Mech Ageing Dev ; 200: 111594, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34756926

RESUMO

Aging is associated with hypertension and brain blood flow dysregulation, which are major risk factors for cardiovascular and neurodegenerative diseases. Structural remodeling, endothelial dysfunction, or hypercontractility of resistance vessels may cause increased total peripheral resistance and hypertension. Recent studies showed that G protein- and RhoA/Rho-kinase pathways are involved in increased mean arterial pressure (MAP) and arterial tone in middle-aged mice. We aimed to characterize the age-dependent changes in the vascular proteome in normal laboratory mice using mass spectrometry and bioinformatics analyses on middle cerebral arteries and mesenteric resistance arteries from young (3 months) vs. middle-aged (14 months) mice. In total, 31 proteins were significantly affected by age whereas 172 proteins were differentially expressed by vessel type. Hierarchical clustering revealed that 207 proteins were significantly changed or clustered by age. Vitamin B6 pathway, Biosynthesis of antibiotics, Regulation of actin cytoskeleton and Endocytosis were the top enriched KEGG pathways by age. Several proteins in the RhoA/Rho-kinase pathway changed in a manner consistent with hypertension and dysregulation of cerebral perfusion. Although aging had a less profound effect than vessel type on the resistance artery proteome, regulation of actin cytoskeleton, including the RhoA/Rho-kinase pathway, is an important target for age-dependent hypertension.


Assuntos
Envelhecimento/fisiologia , Artérias Mesentéricas , Artéria Cerebral Média , Proteoma/metabolismo , Resistência Vascular , Proteína rhoA de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Circulação Cerebrovascular , Biologia Computacional/métodos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Espectrometria de Massas/métodos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos , Artéria Cerebral Média/metabolismo , Artéria Cerebral Média/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Quinases Associadas a rho/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 312(5): H1068-H1075, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28341632

RESUMO

Cardiac microvascular obstruction (MVO) after ischemia-reperfusion (I/R) has been well studied, but microvascular leakage (MVL) remains largely unexplored. We characterized MVL in the mouse I/R model by histology, biochemistry, and cardiac magnetic resonance (CMR) imaging. I/R was induced surgically in mice. MVL was determined by administrating the microvascular permeability tracer Evans blue (EB) and/or gadolinium-diethylenetriaminepentaacetic acid contrast. The size of MVL, infarction, and MVO in the heart was quantified histologically. Myocardial EB was extracted and quantified chromatographically. Serial CMR images were acquired from euthanized mice to determine late gadolinium enhancement (LGE) for comparison with MVL quantified by histology. I/R resulted in MVL with its severity dependent on the ischemic duration and reaching its maximum at 24-48 h after reperfusion. The size of MVL correlated with the degree of left ventricular dilatation and reduction in ejection fraction. Within the risk zone, the area of MVL (75 ± 2%) was greater than that of infarct (47 ± 4%, P < 0.01) or MVO (36 ± 4%, P < 0.01). Contour analysis of paired CMR-LGE by CMR and histological MVL images revealed a high degree of spatial colocalization (r = 0.959, P < 0.0001). These data indicate that microvascular barrier function is damaged after I/R leading to MVL. Histological and biochemical means are able to characterize MVL by size and severity while CMR-LGE is a potential diagnostic tool for MVL. The size of ischemic myocardium exhibiting MVL was greater than that of infarction and MVO, implying a role of MVL in postinfarct pathophysiology.NEW & NOTEWORTHY We characterized, for the first time, the features of microvascular leakage (MVL) as a consequence of reperfused myocardial infarction. The size of ischemic myocardium exhibiting MVL was significantly greater than that of infarction or no reflow. We made a proof-of-concept finding on the diagnostic potential of MVL by cardiac magnetic resonance imaging.


Assuntos
Hemorragia/diagnóstico por imagem , Hemorragia/patologia , Imagem Cinética por Ressonância Magnética/métodos , Microvasos/patologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Animais , Permeabilidade Capilar , Hemorragia/etiologia , Masculino , Camundongos Endogâmicos C57BL , Microvasos/diagnóstico por imagem , Infarto do Miocárdio/complicações , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
4.
Nat Med ; 10(10): 1067-73, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15448684

RESUMO

Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.


Assuntos
Metabolismo Energético/genética , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica , Leptina/metabolismo , Neuropeptídeos/metabolismo , Obesidade/fisiopatologia , Transdução de Sinais/fisiologia , Tecido Adiposo/patologia , Análise de Variância , Animais , Análise Química do Sangue , Northern Blotting , Composição Corporal/genética , Composição Corporal/fisiologia , Regulação da Temperatura Corporal/genética , Peso Corporal/genética , Peso Corporal/fisiologia , Proteínas de Transporte/metabolismo , Metabolismo Energético/fisiologia , Técnicas Histológicas , Hipotálamo/patologia , Imuno-Histoquímica , Hibridização In Situ , Canais Iônicos , Leptina/sangue , Fígado/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Proteínas Mitocondriais , Neuropeptídeos/genética , Obesidade/genética , Proteína Desacopladora 1
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