RESUMO
Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to CVD risk. Previous studies demonstrate that concentrated ambient PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and vascular endothelial growth factor (VEGF) signaling dependent on pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 days) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wild-type (WT) littermates to CAP at concentrations of either â¼60 µg/m3 (CAP60) or â¼100 µg/m3 (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology.NEW & NOTEWORTHY We found that circulating plasma constituents are responsible for air pollution-induced vascular pathologies. Inhalation of fine particulate matter (≤PM2.5) promotes a unique form of dyslipidemia that manifests in a manner dependent upon pulmonary oxidative stress. The air pollution-engendered dyslipidemic phenotype is characterized by elevated free fatty acid species and diminished phospholipid species, which could contribute to vascular inflammation and loss of insulin sensitivity.
Assuntos
Poluentes Atmosféricos/toxicidade , Aorta/efeitos dos fármacos , Aortite/induzido quimicamente , Dislipidemias/induzido quimicamente , Resistência à Insulina , Lipídeos/sangue , Metaboloma , Material Particulado/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Aortite/sangue , Aortite/patologia , Biomarcadores/sangue , Células Cultivadas , Dislipidemias/sangue , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Exposição por Inalação , Insulina/sangue , Lipidômica , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Environmental air pollution exposure is a leading cause of death worldwide, and with increasing industrialization and urbanization, its disease burden is expected to rise even further. The majority of air pollution exposure-associated deaths are linked to cardiovascular disease (CVD). Although ample research demonstrates a strong correlation between air pollution exposure and CVD risk, the mechanisms by which inhalation of polluted air affects cardiovascular health are not completely understood. Inhalation of environmental air pollution has been associated with endothelial dysfunction, which suggests that air pollution exposure impacts CVD health by inducing endothelial injury. Interestingly, recent studies demonstrate that air pollution exposure affects the number and function of endothelial progenitor cells (EPCs), subpopulations of bone marrow-derived proangiogenic cells that have been shown to play an essential role in maintaining cardiovascular health. In line with their beneficial function, chronically low levels of circulating EPCs and EPC dysfunction (e.g., in diabetic patients) have been associated with vascular dysfunction, poor cardiovascular health, and increases in the severity of cardiovascular outcomes. In contrast, treatments that improve EPC number and function (e.g., exercise) have been found to attenuate cardiovascular dysfunction. Considering the critical, nonredundant role of EPCs in maintaining vascular health, air pollution exposure-induced impairments in EPC number and function could lead to endothelial dysfunction, consequently increasing the risk for CVD. This review article covers novel aspects and new mechanistic insights of the adverse effects of air pollution exposure on cardiovascular health associated with changes in EPC number and function.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Sistema Cardiovascular/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Sistema Cardiovascular/fisiopatologia , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Humanos , Fenótipo , Medição de Risco , Fatores de Risco , Transdução de SinaisRESUMO
OBJECTIVE: Exposure to fine particulate matter (PM2.5) air pollution is associated with the depletion of circulating endothelial progenitor cells (EPCs), as well as vascular injury and dysfunction. Nevertheless, it remains unclear whether PM2.5 exposure leads to significant impairments in EPC function. Hence, we studied the effects of PM2.5 on EPC-mediated recovery of vascular perfusion after hindlimb ischemia and examined the mechanisms whereby PM2.5 exposure affects EPC abundance and function. APPROACH AND RESULTS: In comparison with EPCs isolated from mice breathing filtered air, EPCs from mice exposed for 9 consecutive days (6 hours per day) to concentrated ambient PM2.5 (CAP) had defects in both proliferation and tube formation. However, CAP exposure of mice overexpressing extracellular superoxide dismutase (ecSOD-Tg) in the lungs did not affect EPC tube formation. Exposure to CAP also suppressed circulating EPC levels, VEGF (vascular endothelial growth factor)-stimulated aortic Akt phosphorylation, and plasma NO levels in wild-type but not in ecSOD-Tg mice. EPCs from CAP-exposed wild-type mice failed to augment basal recovery of hindlimb perfusion when injected into unexposed mice subjected to hindlimb ischemia; however, these deficits in recovery of hindlimb perfusion were absent when using EPCs derived from CAP-exposed ecSOD-Tg mice. The improved reparative function of EPCs from CAP-exposed ecSOD-Tg mice was also reflected by greater expression of Mmp-9 and Nos3 when compared with EPCs from CAP-exposed wild-type mice. CONCLUSIONS: Exposure to PM2.5 impairs EPC abundance and function and prevents EPC-mediated vascular recovery after hindlimb ischemia. This defect is attributed, in part, to pulmonary oxidative stress and was associated with vascular VEGF resistance and a decrement in NO bioavailability.
Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/transplante , Exposição por Inalação/efeitos adversos , Isquemia/cirurgia , Pulmão/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Membro Posterior , Isquemia/metabolismo , Isquemia/patologia , Isquemia/fisiopatologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho da Partícula , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, and diabetes. The multifunctional GST pi-isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet in wild-type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose levels, or insulin levels in mice maintained on a normal chow diet; however, compared with WT mice, the GSTP-null mice were glucose intolerant. In GSTP-null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs, and glucose-6-phosphatase proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes.
Assuntos
Gluconeogênese/fisiologia , Intolerância à Glucose/metabolismo , Glutationa Transferase/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/metabolismo , Animais , Antracenos/farmacologia , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Gluconeogênese/efeitos dos fármacos , Intolerância à Glucose/genética , Glutationa Transferase/genética , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Fígado/efeitos dos fármacos , Camundongos , Camundongos KnockoutRESUMO
Type 2 diabetes is associated with increased mortality and progression to heart failure. Recent studies suggest that diabetes also impairs reparative responses after cell therapy. In this study, we examined potential mechanisms by which diabetes affects cardiac progenitor cells (CPCs). CPCs isolated from the diabetic heart showed diminished proliferation, a propensity for cell death, and a pro-adipogenic phenotype. The diabetic CPCs were insulin-resistant, and they showed higher energetic reliance on glycolysis, which was associated with up-regulation of the pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). In WT CPCs, expression of a mutant form of PFKFB, which mimics PFKFB3 activity and increases glycolytic rate, was sufficient to phenocopy the mitochondrial and proliferative deficiencies found in diabetic cells. Consistent with activation of phosphofructokinase in diabetic cells, stable isotope carbon tracing in diabetic CPCs showed dysregulation of the pentose phosphate and glycero(phospho)lipid synthesis pathways. We describe diabetes-induced dysregulation of carbon partitioning using stable isotope metabolomics-based coupling quotients, which relate relative flux values between metabolic pathways. These findings suggest that diabetes causes an imbalance in glucose carbon allocation by uncoupling biosynthetic pathway activity, which could diminish the efficacy of CPCs for myocardial repair.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicólise , Mioblastos Cardíacos/metabolismo , Fosfofrutoquinase-2/biossíntese , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação Enzimológica da Expressão Gênica , Glucose/genética , Masculino , Camundongos , Mioblastos Cardíacos/patologia , Fosfofrutoquinase-2/genética , Regulação para CimaRESUMO
Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Acrolein (100-275ppm, 10-30min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5-52weeks) were significantly more sensitive to high-level acrolein than age-matched, female WT mice. Both male and female TRPA1-null mice were more sensitive to acrolein-induced mortality than age- and sex-matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1-null than in WT mice. Lung and plasma protein-acrolein adducts were not increased in acrolein-exposed TRPA1-null mice compared with WT mice. To assess TRPA1-dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1-null mice had a slower onset of breathing rate suppression ('respiratory braking') than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200mg/kg) alone or with combined TRPA1 (100mg/kg) and TRPV1 (capsazepine, 10mg/kg) antagonists at 30min post-acrolein exposure (i.e., "real world" delay in treatment) were significantly protected from acrolein-induced mortality. These data show TRPA1 protects against high-level acrolein-induced toxicity in a sex-dependent manner. Post-exposure TRPA1 antagonism also protected against acrolein-induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury.
Assuntos
Acroleína/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/fisiologia , Acroleína/administração & dosagem , Animais , Feminino , Pulmão/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Fatores Sexuais , Canal de Cátion TRPA1RESUMO
RATIONALE: Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. OBJECTIVE: We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury. METHODS AND RESULTS: In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism of 4-hydroxy-trans-2-nonenal or trans-2-hexanal; on ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than wild-type hearts. GSTP deficiency did not affect I/R-induced free radical generation, c-Jun N-terminal kinase activation, or depletion of reduced glutathione. Acrolein exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na(+)/Ca(++) exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than wild-type myocytes to acrolein-induced protein crosslinking and cell death. CONCLUSIONS: GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.
Assuntos
Glutationa Transferase/deficiência , Glutationa Transferase/genética , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Miocárdio/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologiaRESUMO
Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1ß and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution.
Assuntos
Aorta/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Insulina/farmacologia , Metformina/farmacologia , Material Particulado/toxicidade , Tiazolidinedionas/farmacologia , Animais , Aorta/metabolismo , Ataxina-1/metabolismo , Caspase 1/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Células Progenitoras Endoteliais/metabolismo , Homeostase , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Exposição por Inalação/efeitos adversos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rosiglitazona , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100-300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK · MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein-acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1-5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10-20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Ciclofosfamida/toxicidade , Glutationa Transferase/genética , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Acroleína/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Ecocardiografia , Glutationa Transferase/metabolismo , Glutationa Transferase/fisiologia , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miocárdio/enzimologiaRESUMO
Lipid peroxidation products, such as 4-hydroxy-trans-2-nonenal (HNE), cause endothelial activation, and they increase the adhesion of the endothelium to circulating leukocytes. Nevertheless, the mechanisms underlying these effects remain unclear. We observed that in HNE-treated human umbilical vein endothelial cells, some of the protein-HNE adducts colocalize with the endoplasmic reticulum (ER) and that HNE forms covalent adducts with several ER chaperones that assist in protein folding. We also found that at concentrations that did not induce apoptosis or necrosis, HNE activated the unfolded protein response, leading to an increase in XBP-1 splicing, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α, and the induction of ATF3 and ATF4. This increase in eukaryotic translation initiation factor 2α phosphorylation was prevented by transfection with protein kinase-like ER kinase siRNA. Treatment with HNE increased the expression of the ER chaperones, GRP78 and HERP. Exposure to HNE led to a depletion of reduced glutathione and an increase in the production of reactive oxygen species (ROS); however, glutathione depletion and ROS production by tert-butyl-hydroperoxide did not trigger the unfolded protein response. Pretreatment with a chemical chaperone, phenylbutyric acid, or adenoviral transfection with ATF6 attenuated HNE-induced monocyte adhesion and IL-8 induction. Moreover, phenylbutyric acid and taurine-conjugated ursodeoxycholic acid attenuated HNE-induced leukocyte rolling and their firm adhesion to the endothelium in rat cremaster muscle. These data suggest that endothelial activation by HNE is mediated in part by ER stress, induced by mechanisms independent of ROS production or glutathione depletion. The induction of ER stress may be a significant cause of vascular inflammation induced by products of oxidized lipids.
Assuntos
Aldeídos/metabolismo , Aldeídos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Peroxidação de Lipídeos , Sequência de Aminoácidos , Animais , Chaperona BiP do Retículo Endoplasmático , Endotélio/citologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Glutationa/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Dados de Sequência Molecular , Transporte Proteico/efeitos dos fármacos , Proteínas/química , Proteínas/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
Fine particulate matter (PM2.5) air pollution exposure increases the cardiovascular disease risk. Although the specific mechanisms remain elusive, it is thought that PM2.5-induced oxidative stress and endothelial dysfunction contribute to this pathogenesis. Our previous findings indicate that PM2.5 impairs vascular health via a circulating factor and that plasma lipid changes contribute to the observed vascular effects. In the current study, we extend on these findings by further characterizing PM2.5-induced changes in circulating lipids and examining whether the observed changes were accompanied by related alterations in the liver transcriptome. To address the role of pulmonary oxidative stress, we exposed wild-type (WT) mice and mice that overexpress extracellular superoxide dismutase (ecSOD-Tg) in the lungs to concentrated ambient PM2.5 (CAP, 9 days). We found that CAP decreased circulating complex lipids and increased free fatty acids and acylcarnitines in WT, but not ecSOD-Tg mice. These plasma lipid changes were accompanied by transcriptional changes in genes that regulate lipid metabolism (e.g., upregulation of lipid biosynthesis, downregulation of mitochondrial/peroxisomal FA metabolism) in the liver. The CAP-induced changes in lipid homeostasis and liver transcriptome were accompanied by pulmonary but not hepatic oxidative stress and were largely absent in ecSOD-Tg mice. Our results suggest that PM2.5 impacts hepatic lipid metabolism; however, it remains unclear whether the transcriptional changes in the liver contribute to PM2.5-induced changes in plasma lipids. Regardless, PM2.5-induced changes in the plasma lipidome and hepatic transcriptome are, at least in part, mediated by pulmonary oxidative stress.
RESUMO
Results of human and animal studies independently suggest that either ambient fine particulate matter (PM2.5) air pollution exposure or a disturbed circadian rhythm (circadian dyssynchrony) are important contributing factors to the rapidly evolving type-2-diabetes (T2D) epidemic. The objective of this study is to investigate whether circadian dyssynchrony increases the susceptibility to PM2.5 and how PM2.5 affects metabolic health in circadian dyssynchrony. We examined systemic and organ-specific changes in glucose homeostasis and insulin sensitivity in mice maintained on a regular (12/12 h light/dark) or disrupted (18/6 h light/dark, light-induced circadian dyssynchrony, LICD) light cycle exposed to air or concentrated PM2.5 (CAP, 6 h/day, 30 days). Exposures during Zeitgeber ZT3-9 or ZT11-17 (Zeitgeber in circadian time, ZT0 = begin of light cycle) tested for time-of-day PM2.5 sensitivity (chronotoxicity). Mice transgenic for lung-specific overexpression of extracellular superoxide dismutase (ecSOD-Tg) were used to assess the contribution of CAP-induced pulmonary oxidative stress. Both, CAP exposure from ZT3-9 or ZT11-17, decreased glucose tolerance and insulin sensitivity in male mice with LICD, but not in female mice or in mice kept on a regular light cycle. Although changes in glucose homeostasis in CAP-exposed male mice with LICD were not associated with obesity, they were accompanied by white adipose tissue (WAT) inflammation, impaired insulin signaling in skeletal muscle and liver, and systemic and pulmonary oxidative stress. Preventing CAP-induced oxidative stress in the lungs mitigated the CAP-induced decrease in glucose tolerance and insulin sensitivity in LICD. Our results demonstrate that circadian dyssynchrony is a novel susceptibility state for PM2.5 and suggest that PM2.5 by inducing pulmonary oxidative stress increases glucose intolerance and insulin resistance in circadian dyssynchrony.
Assuntos
Poluentes Atmosféricos , Intolerância à Glucose , Resistência à Insulina , Humanos , Masculino , Feminino , Camundongos , Animais , Material Particulado/toxicidade , Material Particulado/metabolismo , Intolerância à Glucose/induzido quimicamente , Pulmão , Estresse Oxidativo , Glucose/metabolismo , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/metabolismoRESUMO
Increased adiposity of both visceral and perivascular adipose tissue (PVAT) depots is associated with an increased risk of diabetes and cardiovascular disease (CVD). Under healthy conditions, PVAT modulates vascular tone via the release of PVAT-derived relaxing factors, including adiponectin and leptin. However, when PVAT expands with high-fat diet (HFD) feeding, it appears to contribute to the development of endothelial dysfunction (ED). Yet, the mechanisms by which PVAT alters vascular health are unclear. Aldose reductase (AR) catalyzes glucose reduction in the first step of the polyol pathway and has been long implicated in diabetic complications including neuropathy, retinopathy, nephropathy, and vascular diseases. To better understand the roles of both PVAT and AR in HFD-induced ED, we studied structural and functional changes in aortic PVAT induced by short-term HFD (60% kcal fat) feeding in wild type (WT) and aldose reductase-null (AR-null) mice. Although 4 weeks of HFD feeding significantly increased body fat and PVAT mass in both WT and AR-null mice, HFD feeding induced ED in the aortas of WT mice but not of AR-null mice. Moreover, HFD feeding augmented endothelial-dependent relaxation in aortas with intact PVAT only in WT and not in AR-null mice. These data indicate that AR mediates ED associated with short-term HFD feeding and that ED appears to provoke 'compensatory changes' in PVAT induced by HFD. As these data support that the ED of HFD feeding is AR-dependent, vascular-localized AR remains a potential target of temporally selective intervention.
RESUMO
RATIONALE: Acute and chronic exposures to airborne particulate matter (PM) have been linked in epidemiological studies to a wide spectrum of cardiovascular disorders that are characterized by a dysfunctional endothelium. The pathophysiological mechanisms underlying these associations are unclear. OBJECTIVE: To examine whether exposure to fine PM with an aerodynamic diameter of <2.5 microm (PM(2.5)) affects the circulating levels of endothelial progenitor cell (EPC) populations, systemic inflammation and coagulation. METHODS AND RESULTS: Phenotypically distinct EPC populations were quantified by flow cytometry in young (18 to 25 years) adult humans exposed to episodic increases in PM(2.5) along the Wasatch Mountain Front in Utah. In addition, Sca-1+/Flk-1+ cells were measured in the peripheral blood of mice exposed to concentrated particles from ambient air in Louisville, Ky. In both studies, PM exposure was negatively correlated with circulating EPC levels. In humans, statistically significant associations between PM(2.5) exposure and the plasma levels of platelet-monocyte aggregates, high-density lipoprotein, and nonalbumin protein were also observed. Episodic increases in PM(2.5) did not change plasma levels of C-reactive protein, interleukin-1beta, interleukin-6, fibrinogen, or serum amyloid A. CONCLUSIONS: Episodic exposure to PM(2.5) induces reversible vascular injury, reflected in part by depletion of circulating EPC levels, and increases in platelet activation and the plasma level of high-density lipoprotein. These changes were also accompanied by an increase in nonalbumin protein and may be related to mechanisms by which exposure to particulate air pollution increases the risk of cardiovascular disease and adverse cardiovascular events.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Material Particulado/efeitos adversos , Células-Tronco/efeitos dos fármacos , Adolescente , Adulto , Animais , Antígenos CD/sangue , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/imunologia , HDL-Colesterol/sangue , Regulação para Baixo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Mediadores da Inflamação/sangue , Kentucky , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Fenótipo , Adesividade Plaquetária/efeitos dos fármacos , Albumina Sérica/metabolismo , Células-Tronco/imunologia , Células-Tronco/metabolismo , Fatores de Tempo , Utah , Adulto JovemRESUMO
OBJECTIVE: Acrolein is a toxic chemical present in tobacco, wood, and coal smoke, as well as automobile exhaust. Because exposure to these pollutants is associated with an increase in cardiovascular disease risk, we studied the effects of acrolein on Flk-1(+)/Sca-1(+) cells that are involved in vascular repair. METHODS AND RESULTS: In adult male C57BL/6 mice, inhalation of acrolein (1 part per million [ppm], 6 hours/day for 4 days or 5 ppm for 2 or 6 hours) led to the formation of protein-acrolein adducts in the bone marrow and diminished levels of plasma nitric oxide metabolites and circulating Flk-1(+)/Sca-1(+) but not Sca-1(+)-only cells. Acrolein exposure increased the number of apoptotic Flk-1(+)/Sca-1(+) cells in circulation and increased bone marrow-derived cells with endothelial characteristics (DiI-ac-low-density lipoprotein [DiI-acLDL]/UE-lectin and Flk-1(+)/Sca-1(+)) in culture. Deficits in the circulating levels of Flk-1(+)/Sca-1(+) cells were reversed after 7 days of recovery in acrolein-free air. Exposure to acrolein blocked vascular endothelial growth factor (VEGF)/AMD3100-stimulated mobilization of Flk-1(+)/Sca-1(+) but not Sca-1(+)-only cells and prevented VEGF-induced phosphorylation of Akt and endothelial nitric oxide synthase in the aorta. CONCLUSIONS: Inhalation of acrolein increases apoptosis and suppresses the circulating levels of Flk-1(+)/Sca-1(+) cells while increasing these cells in the bone marrow and preventing their mobilization by VEGF. Exposure to acrolein-rich pollutants could impair vascular repair capacity.
Assuntos
Acroleína/toxicidade , Poluentes Atmosféricos/toxicidade , Antígenos Ly/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Movimento Celular , Células Endoteliais/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Acroleína/administração & dosagem , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Benzilaminas , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Células Cultivadas , Ciclamos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Compostos Heterocíclicos/farmacologia , Exposição por Inalação , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/metabolismo , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/administração & dosagemRESUMO
Environmental triggers of dilated cardiomyopathy are poorly understood. Acute exposure to acrolein, a ubiquitous aldehyde pollutant, impairs cardiac function and cardioprotective responses in mice. Here, we tested the hypothesis that chronic oral exposure to acrolein induces inflammation and cardiomyopathy. C57BL/6 mice were gavage-fed acrolein (1 mg/kg) or water (vehicle) daily for 48 days. The dose was chosen based on estimates of human daily unsaturated aldehyde consumption. Compared with vehicle-fed mice, acrolein-fed mice exhibited significant (P < 0.05) left ventricular (LV) dilatation (LV end-diastolic volume 36 ± 8 vs. 17 ± 5 µl), contractile dysfunction (dP/dt(max) 4,697 ± 1,498 vs. 7,016 ± 1,757 mmHg/s), and impaired relaxation (tau 15.4 ± 4.3 vs. 10.4 ± 2.2 ms). Histological and biochemical evaluation revealed myocardial oxidative stress (membrane-localized protein-4-hydroxy-trans-2-nonenal adducts) and nitrative stress (increased protein-nitrotyrosine) and varying degrees of plasma and myocardial protein-acrolein adduct formation indicative of physical translocation of ingested acrolein to the heart. Acrolein also induced myocyte hypertrophy (~2.2-fold increased myocyte area, P < 0.05), increased apoptosis (~7.5-fold), and disrupted endothelial nitric oxide synthase in the heart. DNA binding studies, immunohistochemistry, and PCR revealed significant (P < 0.05) activation of nuclear factor-κB in acrolein-exposed hearts, along with upregulated gene expression of proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß. Long-term oral exposure to acrolein, at an amount within the range of human unsaturated aldehyde intake, induces a phenotype of dilated cardiomyopathy in the mouse. Human exposure to acrolein may have analogous effects and raise consideration of an environmental, aldehyde-mediated basis for heart failure.
Assuntos
Acroleína/toxicidade , Cardiomiopatia Dilatada/induzido quimicamente , Poluentes Ambientais/toxicidade , Acroleína/administração & dosagem , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Poluentes Ambientais/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miocardite/induzido quimicamente , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Inhalation of (nano)particles may lead to pulmonary inflammation. However, the precise mechanisms of particle uptake and generation of inflammatory mediators by alveolar macrophages (AM) are still poorly understood. The aim of this study was to investigate the interactions between particles and AM and their associated pro-inflammatory effects in relation to particle size and physico-chemical properties.NR8383 rat lung AM were treated with ultrafine (uf), fine (f) TiO2 or fine crystalline silica (DQ12 quartz). Physico-chemical particle properties were investigated by transmission electron microscopy, elemental analysis and thermogravimetry. Aggregation and agglomeration tendency of the particles were determined in assay-specific suspensions by means of dynamic light scattering.All three particle types were rapidly taken up by AM. DQ12 and ufTiO2 , but not fTiO2 , caused increased extracellular reactive oxygen species (ROS), heme oxygenase 1 (HO-1) mRNA expression and tumor necrosis factor (TNF)-α release. Inducible nitric oxide synthase (iNOS) mRNA expression was increased most strongly by ufTiO2 , while DQ12 exclusively triggered interleukin (IL) 1ß release. However, oscillations of intracellular calcium concentration and increased intracellular ROS were observed with all three samples. Uptake inhibition experiments with cytochalasin D, chlorpromazine and a Fcγ receptor II (FcγRII) antibody revealed that the endocytosis of fTiO2 by the macrophages involves actin-dependent phagocytosis and macropinocytosis as well as clathrin-coated pit formation, whereas the uptake of ufTiO2 was dominated by FcγIIR. The uptake of DQ12 was found to be significantly reduced by all three inhibitors. Our findings suggest that the contrasting AM responses to fTiO2 , ufTiO2 and DQ12 relate to differences in the involvement of specific uptake mechanisms.
Assuntos
Poluentes Atmosféricos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Nanopartículas/toxicidade , Titânio/toxicidade , Poluentes Atmosféricos/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Clorpromazina/farmacologia , Citocalasina D/farmacologia , Endocitose/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Nanopartículas/ultraestrutura , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho da Partícula , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de IgG/imunologia , Dióxido de Silício/metabolismo , Dióxido de Silício/toxicidade , Titânio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Exposure to fine particulate matter (PM2.5) air pollution is associated with quantitative deficits of circulating endothelial progenitor cells (EPCs) in humans. Related exposures of mice to concentrated ambient PM2.5 (CAP) likewise reduces levels of circulating EPCs and induces defects in their proliferation and angiogenic potential as well. These changes in EPC number or function are predictive of larger cardiovascular dysfunction. To identify global, PM2.5-dependent mRNA and miRNA expression changes that may contribute to these defects, we performed a transcriptomic analysis of cells isolated from exposed mice. Compared with control samples, we identified 122 upregulated genes and 44 downregulated genes in EPCs derived from CAP-exposed animals. Functions most impacted by these gene expression changes included regulation of cell movement, cell and tissue development, and cellular assembly and organization. With respect to miRNA changes, we found that 55 were upregulated while 53 were downregulated in EPCs from CAP-exposed mice. The top functions impacted by these miRNA changes included cell movement, cell death and survival, cellular development, and cell growth and proliferation. A subset of these mRNA and miRNA changes were confirmed by qRT-PCR, including some reciprocal relationships. These results suggest that PM2.5-induced changes in gene expression may contribute to EPC dysfunction and that such changes may contribute to the adverse cardiovascular outcomes of air pollution exposure.