RESUMEN
The COVID-19 pandemic has highlighted structural inequalities and racism promoting health disparities among communities of color. Taking cardiovascular disease as an example, we provide a framework for multidisciplinary efforts leveraging translational and epidemiologic approaches to decode the biological impacts of inequalities and racism and develop targeted interventions that promote health equity.
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COVID-19/epidemiología , Equidad en Salud , Promoción de la Salud/métodos , Racismo , Estrés Fisiológico/inmunología , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/psicología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/psicología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Regulación de la Expresión Génica/fisiología , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/fisiología , Racismo/psicología , Factores de Riesgo , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/fisiologíaRESUMEN
OBJECTIVE: Neighborhood perceptions are associated with physical and mental health outcomes; however, the biological associates of this relationship remain to be fully understood. Here, we evaluate the relationship between neighborhood perceptions and amygdala activity and connectivity with salience network (i.e., insula, anterior cingulate, thalamus) nodes. METHODS: Forty-eight older adults (mean age = 68 [7] years, 52% female, 47% non-Hispanic Black, 2% Hispanic) without dementia or depression completed the Perceptions of Neighborhood Environment Scale. Lower scores indicated less favorable perceptions of aesthetic quality, walking environment, availability of healthy food, safety, violence (i.e., more perceived violence), social cohesion, and participation in activities with neighbors. Participants separately underwent resting-state functional magnetic resonance imaging. RESULTS: Less favorable perceived safety ( ß = -0.33, pFDR = .04) and participation in activities with neighbors ( ß = -0.35, pFDR = .02) were associated with higher left amygdala activity, independent of covariates including psychosocial factors. Less favorable safety perceptions were also associated with enhanced left amygdala functional connectivity with the bilateral insular cortices and the left anterior insula ( ß = -0.34, pFDR = .04). Less favorable perceived social cohesion was associated with enhanced left amygdala functional connectivity with the right thalamus ( ß = -0.42, pFDR = .04), and less favorable perceptions about healthy food availability were associated with enhanced left amygdala functional connectivity with the bilateral anterior insula (right: ß = -0.39, pFDR = .04; left: ß = -0.42, pFDR = .02) and anterior cingulate gyrus ( ß = -0.37, pFDR = .04). CONCLUSIONS: Taken together, our findings document relationships between select neighborhood perceptions and amygdala activity as well as connectivity with salience network nodes; if confirmed, targeted community-level interventions and existing community strengths may promote brain-behavior relationships.
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Encéfalo , Imagen por Resonancia Magnética , Humanos , Femenino , Anciano , Masculino , Imagen por Resonancia Magnética/métodos , Giro del Cíngulo , Amígdala del Cerebelo/diagnóstico por imagen , Mapeo EncefálicoRESUMEN
Social determinants of health (SDoH), which encompass the economic, social, environmental, and psychosocial factors that influence health, play a significant role in the development of cardiovascular disease (CVD) risk factors as well as CVD morbidity and mortality. The COVID-19 pandemic and the current social justice movement sparked by the death of George Floyd have laid bare long-existing health inequities in our society driven by SDoH. Despite a recent focus on these structural drivers of health disparities, the impact of SDoH on cardiovascular health and CVD outcomes remains understudied and incompletely understood. To further investigate the mechanisms connecting SDoH and CVD, and ultimately design targeted and effective interventions, it is important to foster interdisciplinary efforts that incorporate translational, epidemiological, and clinical research in examining SDoH-CVD relationships. This review aims to facilitate research coordination and intervention development by providing an evidence-based framework for SDoH rooted in the lived experiences of marginalized populations. Our framework highlights critical structural/socioeconomic, environmental, and psychosocial factors most strongly associated with CVD and explores several of the underlying biologic mechanisms connecting SDoH to CVD pathogenesis, including excess stress hormones, inflammation, immune cell function, and cellular aging. We present landmark studies and recent findings about SDoH in our framework, with careful consideration of the constructs and measures utilized. Finally, we provide a roadmap for future SDoH research focused on individual, clinical, and policy approaches directed towards developing multilevel community-engaged interventions to promote cardiovascular health.
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Enfermedades Cardiovasculares/epidemiología , Determinantes Sociales de la Salud/estadística & datos numéricos , Equidad en Salud/estadística & datos numéricos , HumanosRESUMEN
BACKGROUND: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. METHODS: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. RESULTS: Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. CONCLUSION: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.
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Placa Aterosclerótica , Características de la Residencia , Humanos , Femenino , Autopsia , Factores de Riesgo , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Características del Vecindario , Factores SocioeconómicosRESUMEN
While it is well known from numerous epidemiologic investigations that social determinants (socioeconomic, environmental, and psychosocial factors exposed to over the life-course) can dramatically impact cardiovascular health, the molecular mechanisms by which social determinants lead to poor cardiometabolic outcomes are not well understood. This review comprehensively summarizes a variety of current topics surrounding the biological effects of adverse social determinants (i.e., the biology of adversity), linking translational and laboratory studies with epidemiologic findings. With a strong focus on the biological effects of chronic stress, we highlight an array of studies on molecular and immunological signaling in the context of social determinants of health (SDoH). The main topics covered include biomarkers of sympathetic nervous system and hypothalamic-pituitary-adrenal axis activation, and the role of inflammation in the biology of adversity focusing on glucocorticoid resistance and key inflammatory cytokines linked to psychosocial and environmental stressors (PSES). We then further discuss the effect of SDoH on immune cell distribution and characterization by subset, receptor expression, and function. Lastly, we describe epigenetic regulation of the chronic stress response and effects of SDoH on telomere length and aging. Ultimately, we highlight critical knowledge gaps for future research as we strive to develop more targeted interventions that account for SDoH to improve cardiometabolic health for at-risk, vulnerable populations.
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Enfermedades Cardiovasculares , Determinantes Sociales de la Salud , Humanos , Sistema Hipotálamo-Hipofisario , Epigénesis Genética , Sistema Hipófiso-Suprarrenal , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiologíaRESUMEN
There are approximately 38 million people globally living with Human immunodeficiency virus 1 (HIV-1) and given the tremendous success of combination antiretroviral therapy (cART) this has dramatically reduced mortality and morbidity with prevention benefits. However, HIV-1 persists during cART within the human body and re-appears upon cART interruption. This HIV-1 reservoir remains a barrier to cure with cellular sites of viral persistence not fully understood. In this study we provide evidence corroborating a recently published article in STM demonstrating the role of platelets as a novel cellular disseminator of HIV-1 particles in the setting of viral suppression. Using classical transmission electron microscopy with and without immunogold labeling, we visualize HIV-1 in both platelets and monocytes in cART suppressed HIV donors. Our study suggests that due to the close proximity of platelets and monocytes an alternative life cycle of HIV-1 cycling within monocytes and platelets without the need of active replication under cART occurs. Our findings are supported by the lack of detectable HIV-1 particles in platelets derived from HIV uninfected donors or the 'Berlin' patient suggesting that platelets may serve as an underappreciated hidden bearer for HIV-1 and should be considered in HIV remission studies and trials.
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Plaquetas/metabolismo , Infecciones por VIH/sangre , VIH-1/patogenicidad , HumanosRESUMEN
OBJECTIVES: Little is understood about associations between neighborhood characteristics and depression, a cardiovascular disease (CVD) risk factor, in diverse populations. We examined relationships between perceived/objective neighborhood characteristics, depression, and CVD markers within the Washington, DC CV Health/Needs Assessment, an evaluation among predominantly African-American (AA) adults in resource-limited DC communities. METHOD: Factor analysis of overall neighborhood environment perception (NEP) identified three NEP sub-scores:1) violence; 2) physical/social environment; 3) social cohesion (higher score = more favorable perception). Objective neighborhood characteristics were measured by geospatially-derived scores of walkability, transportation, and crime. Depression was defined by the revised Center for Epidemiologic Studies Depression Scale (CESD-R). We used linear-regression modeling to examine neighborhood measures and CESD-R associations. To investigate a subsequent connection with CVD risk, we examined relationships between CESD-R and CVD-associated cytokines in a population subset. RESULTS: Participants (N = 99; mean age = 59.06; 99% AA) had a mean CESD-R score = 5.8(SD = 8.88). In adjusted models, CESD-R scores decreased by 0.20 units (p = 0.01) for every overall NEP unit-increase. Perceived physical/social environment (ß = -0.34, p = 0.04) and social cohesion (ß = -0.82, p = 0.01) were related to CESD-R while perceived violence was not (ß = -0.28, p = 0.1). Of objective neighborhood environment measures (i.e. walk, transit, bike, personal crime, and property crime scores), only property crime score was associated with depression (ß = 4.99, p < 0.03). In population subset (n = 42), higher CESD-R associated with higher IL-1ß (ß = 21.25, p < 0.01) and IL-18 (ß = 0.006, p = 0.01). CONCLUSION: Favorable neighborhood perceptions are related to lower depressive symptoms in a predominantly AA cohort from Washington, DC resource-limited communities. Neighborhood perceptions appear to be strongly associated with depressive symptoms compared to objective characteristics. Increasing CESD-R scores were related to higher pro-inflammatory markers. Improving neighborhood perceptions may be beneficial to psychological well-being and CV health for urban minority residents.
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Enfermedades Cardiovasculares , Anciano , Enfermedades Cardiovasculares/epidemiología , Depresión/epidemiología , District of Columbia/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Persona de Mediana Edad , Evaluación de Necesidades , Percepción , Características de la Residencia , Factores de RiesgoRESUMEN
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the world. Given the role of immune cells in atherosclerosis development and progression, effective methods for characterizing immune cell populations are needed, particularly among populations disproportionately at risk for CVD. RESULTS: By using a variety of antibodies combined in one staining protocol, we were able to identify granulocyte, lymphocyte, and monocyte sub-populations by CD-antigen expression from 500 µl of whole blood, enabling a more extensive comparison than what is possible with a complete blood count and differential (CBC). The flow cytometry panel was established and tested in a total of 29 healthy men and women. As a proof of principle, these 29 samples were split by their race/ethnicity: African-Americans (AA) (N = 14) and Caucasians (N = 15). We found in accordance with the literature that AA had fewer granulocytes and more lymphocytes when compared to Caucasians, though the proportion of total monocytes was similar in both groups. Several new differences between AA and Caucasians were noted that had not been previously described. For example, AA had a greater proportion of platelet adhesion on non-classical monocytes when compared to Caucasians, a cell-to-cell interaction described as crucially important in CVD. We also examined our flow panel in a clinical population of AA women with known CVD risk factors (N = 20). Several of the flow cytometry parameters that cannot be measured with the CBC displayed correlations with clinical CVD risk markers. For instance, Framingham Risk Score (FRS) calculated for each participant correlated with immune cell platelet aggregates (PA) (e.g. T cell PA ß = 0.59, p = 0.03 or non-classical monocyte PA ß = 0.54, p = 0.02) after adjustment for body mass index (BMI). CONCLUSION: A flow cytometry panel identified differences in granulocytes, monocytes, and lymphocytes between AA and Caucasians which may contribute to increased CVD risk in AA. Moreover, this flow panel identifies immune cell sub-populations and platelet aggregates associated with CVD risk. This flow cytometry panel may serve as an effective method for phenotyping immune cell populations involved in the development and progression of CVD.
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Volumen Sanguíneo , Enfermedades Cardiovasculares , Negro o Afroamericano , Enfermedades Cardiovasculares/diagnóstico , Femenino , Granulocitos , Humanos , Masculino , Monocitos , Proyectos Piloto , Población BlancaRESUMEN
RATIONALE: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis. OBJECTIVE: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis. METHODS AND RESULTS: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index, and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P <0.05 for all) with significant association of oxidized LDL (ß=0.10; P=0.020) and oxHDL (ß=-0.11; P=0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P=0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P<0.001) and with a concomitant decrease in NCB at 1 year (1.04±0.44 versus 0.95±0.32; P=0.03). CONCLUSIONS: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.
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Lipoproteínas/sangre , Placa Aterosclerótica/sangre , Psoriasis/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/epidemiología , Psoriasis/complicacionesRESUMEN
Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow-derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone Ldlr-/- mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37-expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases.
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Aterosclerosis/inmunología , Hiperlipidemias/inmunología , Interleucina-1/metabolismo , Macrófagos/inmunología , Animales , Células Cultivadas , Citocinas/metabolismo , Dieta Alta en Grasa , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de ÓrganosRESUMEN
OBJECTIVE: Macrophage foam cell formation is a key feature of atherosclerosis. Recent studies have shown that specific microRNAs (miRs) are regulated in modified low-density lipoprotein-treated macrophages, which can affect the cellular cholesterol homeostasis. Undertaking a genome-wide screen of miRs regulated in primary macrophages by modified low-density lipoprotein, miR-302a emerged as a potential candidate that may play a key role in macrophage cholesterol homeostasis. APPROACH AND RESULTS: The objective of this study was to assess the involvement of miR-302a in macrophage lipid homeostasis and if it can influence circulating lipid levels and atherosclerotic development when it is inhibited in a murine atherosclerosis model. We found that transfection of primary macrophages with either miR-302a or anti-miR-302a regulated the expression of ATP-binding cassette (ABC) transporter ABCA1 mRNA and protein. Luciferase reporter assays showed that miR-302a repressed the 3' untranslated regions (UTR) activity of mouse Abca1 by 48% and human ABCA1 by 45%. In addition, transfection of murine macrophages with miR-302a attenuated cholesterol efflux to apolipoprotein A-1 (apoA-1) by 38%. Long-term in vivo administration of anti-miR-302a to mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) fed an atherogenic diet led to an increase in ABCA1 in the liver and aorta as well as an increase in circulating plasma high-density lipoprotein levels by 35% compared with that of control mice. The anti-miR-302a-treated mice also displayed reduced atherosclerotic plaque size by ≈25% and a more stable plaque morphology with reduced signs of inflammation. CONCLUSIONS: These studies identify miR-302a as a novel modulator of cholesterol efflux and a potential therapeutic target for suppressing atherosclerosis.
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Aorta/metabolismo , Enfermedades de la Aorta/sangre , Aterosclerosis/sangre , Colesterol/sangre , Macrófagos/metabolismo , MicroARNs/metabolismo , Regiones no Traducidas 3' , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/prevención & control , Apolipoproteína A-I/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/prevención & control , Células COS , Chlorocebus aethiops , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Homeostasis , Humanos , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Tiempo , TransfecciónRESUMEN
OBJECTIVE: The aim of this study was to investigate the role of cluster of differentiation 43 (CD43), an integral membrane glycoprotein with both proadhesive and antiadhesive activities, in atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice were lethally irradiated and reconstituted with either bone marrow from CD43(-/-) mice or from wild-type controls. We found that mice lacking the CD43 on their leukocytes had significantly less severe atherosclerosis and that, contrary to our expectation, macrophage infiltration into the vessel wall was not affected by the lack of CD43 in the leukocytes. However, we found that CD43 mediates cholesterol homeostasis in macrophages by facilitating cholesterol efflux. This resulted in a significant reduction in storage of cholesterol in the aorta of mice lacking CD43 in the leukocytes. CONCLUSIONS: CD43 may be an important mediator of macrophage lipid homeostasis, thereby affecting macrophage foam cell formation and ultimately atherosclerotic plaque development.
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Aorta/metabolismo , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Leucocitos/metabolismo , Leucosialina/metabolismo , Animales , Aorta/inmunología , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Cultivadas , Colesterol/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Leucocitos/inmunología , Leucosialina/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de TiempoRESUMEN
IL-32 is a multifaceted cytokine with a role in infections, autoimmune diseases, and cancer, and it exerts diverse functions, including aggravation of inflammation and inhibition of virus propagation. We previously identified IL-32 as a critical regulator of endothelial cell (EC) functions, and we now reveal that IL-32 also possesses angiogenic properties. The hyperproliferative ECs of human pulmonary arterial hypertension and glioblastoma multiforme exhibited a markedly increased abundance of IL-32, and, significantly, the cytokine colocalized with integrin αVß3. Vascular endothelial growth factor (VEGF) receptor blockade, which resulted in EC hyperproliferation, increased IL-32 three-fold. Small interfering RNA-mediated silencing of IL-32 negated the 58% proliferation of ECs that occurred within 24 h in scrambled-transfected controls. Reduction of IL-32 neither affected apoptosis (insignificant changes in Bak-1, Bcl-2, Bcl-xL, lactate dehydrogenase, annexin V, and propidium iodide) nor VEGF or TGF-ß levels, but siIL-32-transfected adult and neonatal ECs produced up to 61% less NO, IL-8, and matrix metalloproteinase-9, and up to 3-fold more activin A and endostatin. In coculture-based angiogenesis assays, IL-32γ dose-dependently increased tube formation up to 3-fold; an αVß3 inhibitor prevented this activity and reduced IL-32γ-induced IL-8 by 85%. In matrigel plugs loaded with IL-32γ, VEGF, or vehicle and injected into live mice, we observed the anticipated VEGF-induced increase in neocapillarization (8-fold versus vehicle), but unexpectedly, IL-32γ was equally angiogenic. A second signal such as IFN-γ was required to render cells responsive to exogenous IL-32γ; importantly, this was confirmed using a completely synthetic preparation of IL-32γ. In summary, we add angiogenic properties that are mediated by integrin αVß3 but VEGF-independent to the portfolio of IL-32, implicating a role for this versatile cytokine in pulmonary arterial hypertension and neoplastic diseases.
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Interleucinas/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Activinas/metabolismo , Animales , Apoptosis/fisiología , Células Cultivadas , Endostatinas/metabolismo , Hipertensión Pulmonar Primaria Familiar , Glioblastoma/embriología , Glioblastoma/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Integrina alfaVbeta3/metabolismo , Interferón gamma/metabolismo , Interleucina-8/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Óxidos de Nitrógeno/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice. METHODS AND RESULTS: The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44±9 versus 70±7 mU/mg protein; P=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein; P<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the proinflammatory mediators tumor necrosis factor-α, arginase-2, interleukin-1ß, interleukin-6, and interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (ApoE(-/-)) mice, treatment with RNase1 diminished the increased plasma level of eRNA evidenced after injury. Likewise, RNase1 administration reduced neointima formation in comparison with vehicle-treated ApoE(-/-) controls (25.0±6.2 versus 46.9±6.9×10(3) µm(2), P=0.0339) and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro and inhibited leukocyte recruitment to injured carotid arteries in vivo. CONCLUSIONS: Because eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.
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Líquido Extracelular/fisiología , Placa Aterosclerótica/sangre , ARN/fisiología , Ribonucleasas/fisiología , Animales , Aterosclerosis/sangre , Aterosclerosis/inducido químicamente , Aterosclerosis/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Líquido Extracelular/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/inducido químicamente , Placa Aterosclerótica/tratamiento farmacológico , ARN/sangre , Ribonucleasas/uso terapéuticoRESUMEN
Addressing the need for more equitable cardio-oncology care requires attention to existing disparities in cardio-oncologic disease prevention and outcomes. This is particularly important among those affected by adverse social determinants of health (SDOH). The intricate relationship of SDOH, cancer diagnosis, and outcomes from cardiotoxicities associated with oncologic therapies is influenced by sociopolitical, economic, and cultural factors. Furthermore, mechanisms in cell signaling and epigenetic effects on gene expression link adverse SDOH to cancer and the CVD-related complications of oncologic therapies. To mitigate these disparities, a multifaceted strategy is needed that includes attention to health care access, policy, and community engagement for improved disease screening and management. Interdisciplinary teams must also promote cultural humility and competency and leverage new health technology to foster collaboration in addressing the impact of adverse SDOH in cardio-oncologic outcomes.
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Generally, fasting and refeeding confer anti- and proinflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA sequencing and high-performance liquid chromatography-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G protein-coupled receptor 43 (ffar2) were coordinately and inversely regulated by fasting and refeeding. Propionate and free fatty acid receptor agonists decreased interferon-γ and interleukin-17 and significantly blunted histone deacetylase activity in CD4+ T cells. Furthermore, propionate blunted nuclear factor κB activity and diminished interleukin-6 release. In parallel, propionate reduced phosphorylation of canonical T helper 1 (TH1) and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of free fatty acid receptors significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ TH cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-G protein-coupled receptor linked pathway to regulate CD4+ TH cell immune responsiveness.
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Ácidos Grasos no Esterificados , Propionatos , Humanos , Propionatos/farmacología , Leucocitos Mononucleares , Receptores Acoplados a Proteínas G/genética , ObesidadRESUMEN
BACKGROUND: CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair. METHODS AND RESULTS: We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function. CONCLUSIONS: These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function.
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Tratamiento Basado en Trasplante de Células y Tejidos , Quimiocina CXCL12/farmacología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Ataque Isquémico Transitorio/terapia , Infarto del Miocardio/terapia , Glicoproteínas de Membrana Plaquetaria/farmacología , Proteínas Recombinantes de Fusión/farmacología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/uso terapéutico , Colágeno/metabolismo , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Neovascularización Fisiológica/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/metabolismo , Glicoproteínas de Membrana Plaquetaria/uso terapéutico , Unión Proteica , Receptores CXCR4/metabolismo , Resultado del TratamientoRESUMEN
INTRODUCTION: The connection of the microbiome to human health intersects with the physical environment of humans. Each microbiome location can be influenced by environmental conditions that relate to specific geographical locations, which in turn are influenced by social determinants of health such as a neighbourhood. The objective of this scoping review is to explore the current evidence on the relationships between microbiome and neighbourhood to explain microbiome-related health outcomes. METHODS AND ANALYSIS: Arksey and O'Malley's literature review framework will be employed throughout the process, as well as Page, et al's 2020 Preferred Reporting Items for Systematic Review and Meta-Analysis updated workflow to process search results. The literature search will be completed using PubMed/Medline (NLM), Embase (Elsevier), Web of Science, Core Collection (Clarivate Analytics), Scopus (Elsevier), medRxiv preprint server and Open Science Framework server. The search will be conducted using a list of pre-identified Medical Subject Headings (MeSH) terms relating to neighbourhood, microbiome and individual characteristics. There will be no date or language restrictions used in the search. In order to be included in the study, a piece must include an evaluation of the relationship between microbiome diversity and neighbourhood (including at least one measurement of the neighbourhood and at least one human microbiome site). Excluded from the review will be those works that do not include all of these measures, literature reviews based on secondary sources and postmortem populations with no report of premortem health factors. The review itself will be an iterative process completed by two reviewers, with a third individual identified to break ties. Documents will be undergoing a risk assessment of bias in order for the authors to comment on the quality of the literature in this area. Finally, results will be discussed with identified stakeholders, including individuals connected to neighbourhoods facing structural inequity and experts in the topics of study through a community advisory board, for their feedback and knowledge transfer. ETHICS AND DISSEMINATION: This review does not require ethical approval. Results of this search will be disseminated through peer-reviewed publications. Furthermore, this work is completed in conjunction with a community advisory board so as to ensure dissemination to multiple stakeholders.
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Características del Vecindario , Evaluación de Resultado en la Atención de Salud , Humanos , Proyectos de Investigación , Literatura de Revisión como Asunto , Factores de RiesgoRESUMEN
Social determinants of health (SDoH), or the socioeconomic, environmental, and psychosocial conditions in which individuals spend their daily lives, substantially influence obesity as a cardiovascular disease (CVD) risk factor. The coronavirus disease 2019 (COVID-19) pandemic highlighted the converging epidemics of obesity, CVD, and social inequities globally. Obesity and CVD serve as independent risk factors for COVID-19 severity and lower-resourced populations most impacted by adverse SDoH have the highest COVID-19 mortality rates. Better understanding the interplay between social and biologic factors that contribute to obesity-related CVD disparities are important to equitably address obesity across populations. Despite efforts to investigate SDoH and their biologic effects as drivers of health disparities, the connections between SDoH and obesity remain incompletely understood. This review aims to highlight the relationships between socioeconomic, environmental, and psychosocial factors and obesity. We also present potential biologic factors that may play a role in the biology of adversity, or link SDoH to adiposity and poor adipo-cardiology outcomes. Finally, we provide evidence for multi-level obesity interventions targeting multiple aspects of SDoH. Throughout, we emphasize areas for future research to tailor health equity-promoting interventions across populations to reduce obesity and obesity-related CVD disparities.