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AIMS AND METHOD: We aimed to determine the prevalence of risk factors for obstructive sleep apnoea (OSA) in patients with mild cognitive impairment (MCI) or dementia. Using patient records across a 5 year period, we identified 16 855 patients with dementia or MCI. We gave scores for keywords relating to each modified STOP BANG parameter in patient progress notes. Based on individual scores, we stratified the population into groups with low, intermediate and high risk of OSA. RESULTS: Our population had a high prevalence of risk factors and consequently high risk scores for OSA (18.21% high risk). Parameters directly related to sleep had a low prevalence. CLINICAL IMPLICATIONS: The risk of developing or having OSA is high among patients with MCI and dementia. Low sleep parameter frequency probably suggests poor documentation of sleep rather than true prevalence. Our findings support the implementation of the STOP BANG or a similar screening tool as a standardised method to identify OSA risk in memory clinics.
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AIMS: Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling. METHODS AND RESULTS: We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4-/-) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4-/- mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 µm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4-/- mice (+29% vs. -21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4-/- mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A. CONCLUSION: Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.
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Hipertrofia Ventricular Izquierda/enzimología , Miocitos Cardíacos/enzimología , NADPH Oxidasa 4/metabolismo , Función Ventricular Izquierda , Remodelación Ventricular , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Derivación Arteriovenosa Quirúrgica , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Fibrosis , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/patología , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 4/genética , Fosforilación , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Proteína S6 Ribosómica/metabolismo , Transducción de Señal , Familia-src Quinasas/metabolismoRESUMEN
The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II-induced (Ang II-induced) pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline, whereas Ang II-induced effector T cell (Teff) infiltration was inhibited. To investigate the role of Treg Nox2, we generated a mouse line with CD4-targeted Nox2 deficiency (Nox2fl/flCD4Cre+). These animals showed inhibition of Ang II-induced hypertension and cardiac remodeling related to increased tissue-resident Tregs and reduction in infiltrating Teffs, including Th17 cells. The protection in Nox2fl/flCD4Cre+ mice was reversed by anti-CD25 antibody depletion of Tregs. Mechanistically, Nox2-/y Tregs showed higher in vitro suppression of Teff proliferation than WT Tregs, increased nuclear levels of FoxP3 and NF-κB, and enhanced transcription of CD25, CD39, and CD73. Adoptive transfer of Tregs confirmed that Nox2-deficient cells had greater inhibitory effects on Ang II-induced heart remodeling than WT cells. These results identify a previously unrecognized role of Nox2 in modulating suppression of Tregs, which acts to enhance hypertension and cardiac remodeling.
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Angiotensina II/metabolismo , NADPH Oxidasa 2/metabolismo , Linfocitos T Reguladores/metabolismo , Remodelación Vascular/fisiología , Traslado Adoptivo , Angiotensina II/administración & dosificación , Angiotensina II/toxicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Femenino , Factores de Transcripción Forkhead/metabolismo , Hipertensión/inmunología , Hipertensión/metabolismo , Hipertensión/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Cardiovasculares , Miocardio/inmunología , Miocardio/metabolismo , Miocardio/patología , NADPH Oxidasa 2/deficiencia , NADPH Oxidasa 2/genética , FN-kappa B/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Remodelación Vascular/efectos de los fármacos , Remodelación Vascular/inmunologíaRESUMEN
AIMS: NADPH oxidase-4 (Nox4) is an important reactive oxygen species (ROS) source that is upregulated in the haemodynamically overloaded heart. Our previous studies using global Nox4 knockout (Nox4KO) mice demonstrated a protective role of Nox4 during chronic abdominal aortic banding, involving a paracrine enhancement of myocardial capillary density. However, other authors who studied cardiac-specific Nox4KO mice reported detrimental effects of Nox4 in response to transverse aortic constriction (TAC). It has been speculated that these divergent results are due to cell-specific actions of Nox4 (i.e. cardiomyocyte Nox4 detrimental but endothelial Nox4 beneficial) and/or differences in the model of pressure overload (i.e. abdominal banding vs. TAC). This study aimed to (i) investigate whether the effects of Nox4 on pressure overload-induced cardiac remodelling vary according to the pressure overload model and (ii) compare the roles of cardiomyocyte vs. endothelial cell Nox4. METHODS AND RESULTS: Global Nox4KO mice subjected to TAC developed worse cardiac remodelling and contractile dysfunction than wild-type littermates, consistent with our previous results with abdominal aortic banding. Next, we generated inducible cardiomyocyte-specific Nox4 KO mice (Cardio-Nox4KO) and endothelial-specific Nox4 KO mice (Endo-Nox4KO) and studied their responses to pressure overload. Both Cardio-Nox4KO and Endo-Nox4KO developed worse pressure overload-induced cardiac remodelling and dysfunction than wild-type littermates, associated with significant decrease in protein levels of HIF1α and VEGF and impairment of myocardial capillarization. CONCLUSIONS: Cardiomyocyte as well as endothelial cell Nox4 contributes to protection against chronic hemodynamic overload-induced cardiac remodelling, at least in part through common effects on myocardial capillary density.
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Vasos Coronarios/enzimología , Células Endoteliales/enzimología , Hemodinámica , Hipertrofia Ventricular Izquierda/enzimología , Miocitos Cardíacos/enzimología , NADPH Oxidasa 4/metabolismo , Disfunción Ventricular Izquierda/enzimología , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Aorta Torácica/fisiopatología , Aorta Torácica/cirugía , Capilares/enzimología , Capilares/patología , Capilares/fisiopatología , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Células Endoteliales/patología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ligadura , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/patología , NADPH Oxidasa 4/deficiencia , NADPH Oxidasa 4/genética , Neovascularización Fisiológica , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Hypertension caused by increased renin-angiotensin system activation is associated with elevated reactive oxygen species production. Previous studies implicate NADPH oxidase (Nox) proteins as important reactive oxygen species sources during renin-angiotensin system activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types, including endothelial cells, fibroblasts, immune cells, and microglia. Blood pressure (BP) is regulated at the central nervous system, renal, and vascular levels, but the cell-specific role of Nox2 in BP regulation is unknown. METHODS: We generated a novel mouse model with a floxed Nox2 gene and used Tie2-Cre, LysM Cre, or Cdh5-CreERT2 driver lines to develop cell-specific models of Nox2 perturbation to investigate its role in BP regulation. RESULTS: Unexpectedly, Nox2 deletion in myeloid but not endothelial cells resulted in a significant reduction in basal BP. Both Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM CreNox2KO mice (in which Nox2 was deficient in myeloid cells) had significantly lower BP than littermate controls, whereas basal BP was unaltered in Cdh5-CreERT2 Nox2KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability that dynamically dilated resistance vessels in vivo under basal conditions without a change in renal function. Myeloid-specific Nox2 deletion had no effect on angiotensin II-induced hypertension, which, however, was blunted in Tie2-CreNox2KO mice, along with preservation of endothelium-dependent relaxation during angiotensin II stimulation. CONCLUSIONS: We identify a hitherto unrecognized modulation of basal BP by myeloid cell Nox2, whereas endothelial cell Nox2 regulates angiotensin II-induced hypertension. These results identify distinct cell-specific roles for Nox2 in BP regulation.
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Presión Sanguínea/fisiología , Células Endoteliales/enzimología , Hipertensión/enzimología , Glicoproteínas de Membrana/deficiencia , Células Mieloides/enzimología , NADPH Oxidasas/deficiencia , Angiotensina II/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Espectroscopía de Resonancia por Spin del Electrón/métodos , Células Endoteliales/efectos de los fármacos , Hipertensión/inducido químicamente , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/efectos de los fármacos , NADPH Oxidasa 2RESUMEN
The reactive oxygen species-generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart after myocardial infarction (MI). Mice with cardiomyocyte-targeted Nox4 overexpression (TG) displayed increased macrophages in the heart at baseline, with skewing toward an M2 phenotype compared with wild-type controls (WT). After MI, TG mice had a higher proportion of M2 macrophages along with higher survival, decreased cardiac remodeling, and better contractile function than wild-type mice. The post-MI increase in cardiac matrix metalloproteinase-2 activity was substantially blunted in TG mice. These results indicate that cardiomyocyte Nox4 modulates macrophage polarization toward an M2 phenotype, resulting in improved post-MI survival and remodeling, likely through the attenuation of cardiac matrix metalloproteinase-2 activity.
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BACKGROUND: Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. METHODS AND RESULTS: Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. CONCLUSIONS: The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI.
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Trasplante de Médula Ósea , Rotura Cardíaca/prevención & control , Macrófagos/patología , Infarto del Miocardio/patología , Recuperación de la Función , Animales , Vasos Coronarios , Diástole , Femenino , Rotura Cardíaca/metabolismo , Rotura Cardíaca/mortalidad , Rotura Cardíaca/patología , Hemosiderina/metabolismo , Ligadura , Activación de Macrófagos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Infarto del Miocardio/mortalidad , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenotipo , Volumen Sistólico , Análisis de Supervivencia , SístoleRESUMEN
Redox signaling refers to the specific and usually reversible oxidation/reduction modification of molecules involved in cellular signaling pathways. In the heart, redox signaling regulates several physiological processes (eg, excitation-contraction coupling) and is involved in a wide variety of pathophysiological and homoeostatic or stress response pathways. Reactive oxygen species involved in cardiac redox signaling may derive from many sources, but NADPH oxidases, as dedicated sources of signaling reactive oxygen species, seem to be especially important. An increasing number of specific posttranslational oxidative modifications involved in cardiac redox signaling are being defined, along with the reactive oxygen species sources that are involved. Here, we review current knowledge on the molecular targets of signaling reactive oxygen species in cardiac cells and their involvement in cardiac physiopathology. Advances in this field may allow the development of targeted therapeutic strategies for conditions such as heart failure as opposed to the general antioxidant approaches that have failed to date.
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Cardiomegalia/metabolismo , Cardiomegalia/patología , Contracción Miocárdica/fisiología , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Animales , Cardiomegalia/fisiopatología , Humanos , NADPH Oxidasas/metabolismo , Oxidación-ReducciónRESUMEN
OBJECTIVE: Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express α(v)ß(3) integrin. We used an α(v) integrin-specific tracer, (99m)Tc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation. METHODS AND RESULTS: The binding of a fluorescent homologue of NC100692 to α(v)ß(3) on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl(2). NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl(2)-exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant difference in normalized α(v), ß(3), or ß(5) mRNA expression between right and left carotid arteries. Finally, NC100692 uptake strongly correlated with macrophage marker expression in carotid arteries. CONCLUSIONS: NC100692 imaging can detect vessel wall inflammation in vivo. If further validated, α(v)-targeted imaging may provide a noninvasive approach for identifying patients who are at high risk for vascular events and tracking the effect of antiinflammatory treatments.