RESUMO
We have recently described a new peptide of the renin-angiotensin system, alamandine, a derivative of angiotensin-(1-7). Mas-related G protein-coupled receptor member D (MrgD) was identified as its receptor. Although similar cardioprotective effects of alamandine to those of angiotensin-(1-7) have been described, the significance of this peptide in heart function is still elusive. We aimed to evaluate the functional role of the alamandine receptor MrgD in the heart using MrgD-deficient mice. MrgD was localized in cardiomyocytes by immunofluorescence using confocal microscopy. High-resolution echocardiography was performed in wild-type and MrgD-deficient mice (2 and 12 wk old) under isoflurane anesthesia. Standard B-mode images were obtained in the right and left parasternal long and short axes for morphological and functional assessment and evaluation of cardiac deformation. Additional heart function evaluation was performed using Langendorff isolated heart preparations and inotropic measurements of isolated cardiomyocytes. Immunofluorescence indicated that the MrgD receptor is expressed in cardiomyocytes, mainly in the membrane and perinuclear and nuclear regions. Echocardiography showed left ventricular remodeling and severe dysfunction in MrgD-deficient mice. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function. Echocardiographic changes were supported by the data obtained in isolated hearts and inotropic measurements in cardiomyocytes. Our data add new evidence for a major role for alamandine/MrgD in the heart. Furthermore, our results indicate that we have identified a new gene implicated in dilated cardiomyopathy, unveiling a new target for translational approaches aimed to treat heart diseases. NEW & NOTEWORTHY The renin-angiotensin system is a key target for cardiovascular therapy. We have recently identified a new vasodepressor/cardioprotective angiotensin, alamandine. Here, we unmasked a key role for its receptor, Mas-related G protein-coupled receptor member D (MrgD), in heart function. The severe dilated cardiomyopathy observed in MrgD-deficient mice warrants clinical and preclinical studies to unveil its potential use in cardiovascular therapy.
Assuntos
Cardiomiopatia Dilatada/genética , Deleção de Genes , Receptores Acoplados a Proteínas G/genética , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptores Acoplados a Proteínas G/metabolismo , Remodelação VentricularRESUMO
Although primate predation is rarely observed, a series of primate anti-predation strategies have been described. Energetic costs of such strategies can vary from high-cost mobbing, via less costly alarm calling, to low-cost furtive concealment. Here we report the anti-predation strategies of red-nosed cuxiú, Chiropotes albinasus, based on direct observations from four study sites in southeastern Brazilian Amazonia. Over a collective period of 1255 fieldwork hours, we observed nine direct interactions between raptors (all potential predators) and red-nosed cuxiús. Of these, one (11%) resulted in predation. Raptors involved were: Harpia harpyja (four events), Leucopternis sp. (two events), Spizaëtus tyrannus (one event), and unidentified large raptors (two events). Predation attempts occurred in flooded-forest and terra firme rainforest, were directed at both adult and non-adult cuxiús, and involved both adult and juvenile raptors. Anti-predation strategies adopted by the cuxiús included: (1) group defence and mobbing behaviour (two occasions), (2) dropping into dense sub-canopy (seven occasions), (3) alarm calling (eight occasions), and (4) fleeing to, and hiding in, dense vegetation (eight occasions). During each encounter at least two of these behaviours were recorded. These are the first published records of predation, predation attempts, and anti-predator behaviour involving red-nosed cuxiú.
Assuntos
Espécies em Perigo de Extinção , Reação de Fuga , Falconiformes/fisiologia , Pitheciidae/fisiologia , Comportamento Predatório , Agressão , Animais , Brasil , Feminino , Cadeia Alimentar , Masculino , CorridaRESUMO
BACKGROUND: In atherosclerotic lesions, cholesterol-laden macrophage foam cells are formed and exposed to M1- and M2-polarizing factors. However, the effects of the polarizing factors on the proinflammatory and the anti-inflammatory potential of foam cells are not known. OBJECTIVE: To investigate the effects of M1- and M2-polarizing factors on the expression of pro- and anti-inflammatory genes in cultured human macrophage foam cells. METHODS AND RESULTS: Human monocytes were differentiated into macrophages in the presence of M-CSF, and then converted into cholesterol-loaded foam cells by incubation with acetylated LDL. The generated macrophages and foam cells were polarized into the M1 phenotype by classical activation with LPS and IFN-γ, or into the M2 phenotype by alternative activation with IL-4. When subjected to the M1-polarizing factors, the macrophages responded by typical upregulation of several key proinflammatory genes (TNFA, IL1B, CXCL8, CCL19, and COX2), while the anti-inflammatory genes (MRC1, CCL17, and IL10) displayed variable responses. The foam cells, again, showed a weaker response to the M1-polarizing factors, as indicated by reduced upregulation of the proinflammatory genes, reduced secretion of TNF-α, and a trend towards lower NF-κB activity. When subjected to alternative M2 polarization, both macrophages and foam cells responded by a typical upregulation of the anti-inflammatory genes, which was of equal magnitude in both cell types. CONCLUSIONS: Conversion of cultured human macrophages into foam cells suppresses their proinflammatory responses to M1-polarizing factors. Thus, in M1-polarizing microenvironments of atherosclerotic lesions, foam cell formation may locally weaken the macrophage-dependent inflammatory component of atherogenesis.
Assuntos
Células Espumosas/citologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Anti-Inflamatórios/química , Aterosclerose/metabolismo , Colesterol/química , Colesterol/metabolismo , Meios de Cultura Livres de Soro , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/química , Macrófagos/metabolismo , NF-kappa B/metabolismo , Fenótipo , Regulação para CimaRESUMO
AIMS: Wall shear stress differentially regulates the arginase pathway in carotid arteries perfused ex vivo. Specific patterns of wall shear stress can locally determine atherosclerotic plaque size and composition in vivo. The present work investigates the effects of arginase inhibition on shear stress induced plaque composition. METHODS AND RESULTS: Carotid arteries of apolipoprotein E deficient mice were exposed to high (HSS), low (LSS) and oscillatory (OSS) shear stress conditions by the placement of a local shear stress modifier device for 9 weeks with or without the administration of the arginase inhibitor N-ω-Hydroxy-nor-L-arginine (nor-Noha) (10 mg/kg, i.p., 5 days/week). Carotid arginase activity was measured by colorimetric determination of urea. Atherosclerotic plaque size and composition, arginase expression and cellular localization were assessed by immunohistochemistry. Arginase activity was significantly increased in both LSS and OSS regions as compared to HSS. In the lesions, arginase II isoform co-localized preferentially with EC. Inhibition of arginase by nor-Noha decreased arginase activity and reduced plaque size in both LSS and OSS regions. Arginase inhibition affected mainly the composition of plaques developed in LSS regions by decreasing the total vascular ROS, the number of macrophages, apoptosis rate, lipid and collagen contents. CONCLUSIONS: Arginase activity is modulated by patterns of wall shear stress in vivo. Chronic inhibition of vascular arginase decreased the size of atherosclerotic lesions in both OSS and LSS regions, whereas changes on plaque composition were more pronounced in plaques induced by LSS. We identified wall shear stress as a key biomechanical regulator of arginase during plaque formation and stability.