RESUMEN
BACKGROUND: Dog ownership has been associated with decreased cardiovascular risk. Recent reports have suggested an association of dog companionship with lower blood pressure levels, improved lipid profile, and diminished sympathetic responses to stress. However, it is unclear if dog ownership is associated with improved survival as previous studies have yielded inconsistent results. Thus, we performed a systematic review and meta-analysis to evaluate the association of dog ownership with all-cause mortality, with and without prior cardiovascular disease, and cardiovascular mortality. METHODS AND RESULTS: Studies published between 1950 and May 24, 2019 were identified by searching Embase and PubMed. Observational studies that evaluated baseline dog ownership and subsequent all-cause mortality or cardiovascular mortality. Two independent reviewers extracted the data. We assessed pooled data using random-effects model. A possible limitation was that the analyses were not adjusted for confounders. Ten studies were included yielding data from 3 837 005 participants (530 515 events; mean follow-up 10.1 years). Dog ownership was associated with a 24% risk reduction for all-cause mortality as compared to nonownership (relative risk, 0.76; 95% CI, 0.67-0.86) with 6 studies demonstrating significant reduction in the risk of death. Notably, in individuals with prior coronary events, living in a home with a dog was associated with an even more pronounced risk reduction for all-cause mortality (relative risk, 0.35; 95% CI, 0.17-0.69; I2, 0%). Moreover, when we restricted the analyses to studies evaluating cardiovascular mortality, dog ownership conferred a 31% risk reduction for cardiovascular death (relative risk, 0.69; 95% CI, 0.67-0.71; I2, 5.1%). CONCLUSIONS: Dog ownership is associated with lower risk of death over the long term, which is possibly driven by a reduction in cardiovascular mortality. Systematic Review Registration URL: http://www.crd.york.ac.uk/prospero/. Unique identifier: CRD42018111048.
Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Estilo de Vida Saludable , Mascotas , Conducta de Reducción del Riesgo , Adulto , Anciano , Animales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/psicología , Enfermedades Cardiovasculares/terapia , Causas de Muerte , Perros , Ejercicio Físico , Femenino , Conocimientos, Actitudes y Práctica en Salud , Vínculo Humano-Animal , Humanos , Masculino , Persona de Mediana Edad , Motivación , Pronóstico , Factores Protectores , Medición de Riesgo , Factores de Riesgo , Apoyo SocialRESUMEN
Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA. ET-1 immunostaining was localized to macrophage-rich regions in aneurysmal vessels. ERA did not prevent AngII-induced aneurysm formation but instead may have increased aneurysm incidence. In AngII-treated animals with aneurysms, ERA had a profound effect on the non-aneurysmal thoracic aorta via increasing wall thickness, collagen/elastin ratio, wall stiffness, and viscous responses. These observations were confirmed in acute in vitro collagen sheet production models in which ERA inhibited AngII's dose-dependent effect on collagen type 1 α 1 (COL1A1) gene transcription. However, chronic treatment reduced matrix metalloproteinase 2 mRNA expression but enhanced COL3A1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 mRNA expressions. These data confirm a role for the ET system in AngII-accelerated atherosclerosis but suggest that ERA therapy is not protective against the formation of AngII-induced aneurysms and can paradoxically stimulate a chronic arterial matrix remodeling response.
Asunto(s)
Angiotensina II/efectos adversos , Aneurisma de la Aorta/inducido químicamente , Apolipoproteínas E , Aterosclerosis/inducido químicamente , Endotelina-1/fisiología , Vasoconstrictores/efectos adversos , Animales , Antihipertensivos/farmacología , Aorta/fisiología , Fenómenos Biomecánicos , Bosentán , Fármacos Cardiovasculares/farmacología , Adhesión Celular , Colágeno/metabolismo , Regulación hacia Abajo , Endotelina-1/antagonistas & inhibidores , Endotelina-1/biosíntesis , Integrina beta1/metabolismo , Interferón gamma/metabolismo , Ratones , Ratones Noqueados , Estrés Fisiológico , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone). METHODS AND RESULTS: We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice. CONCLUSIONS: We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.
Asunto(s)
Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Resistencia a la Insulina , PPAR gamma/metabolismo , Adiponectina/sangre , Adiponectina/farmacología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Apolipoproteínas E/farmacología , Becaplermina , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dieta , Modelos Animales de Enfermedad , Femenino , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/fisiopatología , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , PPAR gamma/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteínas Proto-Oncogénicas c-sis , Factores de Riesgo , Rosiglitazona , Factores Sexuales , Tiazolidinedionas/farmacologíaRESUMEN
RATIONALE: The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. OBJECTIVES: We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury. METHODS: We used cell-based gene therapy in a rat model of ALI. Transgenic mice overexpressing Ang-1 or deficient in the Tie2 receptor were also studied to better elucidate the mechanisms of protection. MEASUREMENTS AND MAIN RESULTS: The present report provides data that support a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced acute lung injury. In a rat model, cell-based Ang-1 gene transfer improved morphological, biochemical, and molecular indices of lung injury and inflammation. These findings were confirmed in a gain-of-function conditional, targeted transgenic mouse model, in which Ang-1 reduced endothelial cell activation and the expression of adhesion molecules, associated with a marked improvement in airspace inflammation and intraalveolar septal thickening. Moreover, heterozygous Tie2-deficient mice demonstrated enhanced evidence of lung injury and increased early mortality. CONCLUSIONS: These results support a critical role for the Ang-1/Tie2 axis in modulating the pulmonary vascular response to lung injury and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress syndrome in critically ill patients.
Asunto(s)
Angiopoyetina 1/genética , Terapia Genética/métodos , Síndrome de Dificultad Respiratoria/terapia , Animales , Adhesión Celular/genética , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Citocinas/metabolismo , Femenino , Fibroblastos/trasplante , Expresión Génica , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Transgénicos , Ratas , Ratas Endogámicas F344 , Receptor TIE-2/genética , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
Endothelin-1 (ET-1) is increasingly recognized as a proinflammatory mediator in various diseases, such as atherosclerosis and acute respiratory distress syndrome (ARDS). Angiopoietin-1 (Ang-1), a ligand of the endothelial receptor Tie2, inhibits endothelial apoptosis, reduces vascular leakage, and suppresses the induction of inflammatory markers, indicating that it has diverse vasoprotective, anti-inflammatory actions. Thus, we examined the effects of Ang-1 on ET-1 production in vitro and in vivo and investigated cell-based gene transfer of Ang-1 in a rat model of lipopolysaccharide (LPS)-induced ARDS. Cultured human endothelial cells were treated with recombinant Ang-1 with or without tumor necrosis factor-alpha (TNF-alpha) (100 U/ml). ET-1 release into the culture medium after 24 hrs was determined by enzyme-linked immunosorbent assay. Levels of preproendothelin-1 (ppET-1) mRNA were measured by quantitative reverse transcription-polymerase chain reaction. Fisher344 rats were subjected to cell-based gene transfer to the lung circulation by injecting syngeneic fibroblasts transfected with Ang-1 cDNA or a null plasmid vector. After 24 hrs, LPS (100 microg/kg body wt) was instilled intratracheally to induce pulmonary inflammation. Bronchoalveolar lavage was performed 6 hrs later, and lungs were harvested for histologic and molecular analyses. ET-1 release from cultured endothelial cells was dose-dependently reduced by Ang-1, which also prevented induction of ET-1 release by TNF-alpha (P < 0.05). RNA expression of ppET-1 was similarly reduced. In LPS-challenged lungs, ppET-1 RNA was induced 3.4-fold, and ET-1 protein in lavage fluid was increased 5.6-fold (P < 0.05). Ang-1 gene transfer attenuated the LPS-induced increases in ppET-1 RNA and lavage ET-1 protein by 34% and 33%, respectively (P < 0.05). The downregulation of ET-1 correlated with the amelioration of pulmonary inflammation, as indicated by reductions in leukocyte infiltration (by 43%) and intra-alveolar septal thickening (by 40%). These results show that ET-1 transcript and protein levels are downregulated by Ang-1 in both in vitro and in vivo systems and that cell-based Ang-1 gene transfer markedly ameliorated inflammation in vivo in an experimental model of ARDS. Thus, cell-based gene transfer of Ang-1 may provide a novel treatment strategy for ARDS by attenuating vascular inflammation via suppression of ET-1.