RESUMO
Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure (E/e') and diastolic stiffness [E/e'/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.
Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Feminino , Masculino , Animais , Camundongos , Células Endoteliais/patologia , Insuficiência Cardíaca/complicações , Receptores de Mineralocorticoides/genética , Camundongos Obesos , Proteínas Proto-Oncogênicas c-akt , Volume Sistólico , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Dieta Ocidental , Obesidade/etiologiaRESUMO
BACKGROUND: Bread wheat (Triticum aestivum) is an allohexaploid that is generated by two subsequent allopolyploidization events. The large genome size (16 Gb) and polyploid complexity impede our understanding of how regulatory elements and their interactions shape chromatin structure and gene expression in wheat. The open chromatin enrichment and network Hi-C (OCEAN-C) is a powerful antibody-independent method to detect chromatin interactions between open chromatin regions throughout the genome. RESULTS: Here we generate open chromatin interaction maps for hexaploid wheat and its tetraploid and diploid relatives using OCEAN-C. The anchors of chromatin loops show high chromatin accessibility and are concomitant with several active histone modifications, with 67% of them interacting with multiple loci. Binding motifs of various transcription factors are significantly enriched in the hubs of open chromatin interactions (HOCIs). The genes linked by HOCIs represent higher expression level and lower coefficient expression variance than the genes linked by other loops, which suggests HOCIs may coordinate co-expression of linked genes. Thousands of interchromosomal loops are identified, while limited interchromosomal loops (0.4%) are identified between homoeologous genes in hexaploid wheat. Moreover, we find structure variations contribute to chromatin interaction divergence of homoeologs and chromatin topology changes between different wheat species. The genes with discrepant chromatin interactions show expression alteration in hexaploid wheat compared with its tetraploid and diploid relatives. CONCLUSIONS: Our results reveal open chromatin interactions in different wheat species, which provide new insights into the role of open chromatin interactions in gene expression during the evolution of polyploid wheat.
Assuntos
Cromatina , Triticum , Cromatina/metabolismo , Cromossomos , Genoma de Planta , Poliploidia , Triticum/genética , Triticum/metabolismoRESUMO
Consumption of diets high in fat, sugar, and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Women with obesity are more prone to develop arterial stiffening leading to more frequent and severe CVD compared with men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a nonspecific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 wk starting at 4 wk of age. The second was fed a WD for the same 43 wk, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/day) in the drinking water during the last 8 wk on the diet (WD + C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- versus CD-fed mice, and reduced in WD + C versus WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin:G-actin ratio, collagen compaction capacity, and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely because of its TG2 inhibitory capacity.NEW & NOTEWORTHY This study evaluates the novel role of transglutaminase 2 (TG2) inhibition to directly treat vascular stiffness. Our data demonstrate that cystamine, a nonspecific TG2 inhibitor, improves vascular stiffness induced by a diet rich in fat, fructose, and salt. This research suggests that TG2 inhibition might bear therapeutic potential to reduce the disproportionate burden of cardiovascular disease in females in conditions of chronic overnutrition.
Assuntos
Cistamina/farmacologia , Dieta Ocidental/efeitos adversos , Inibidores Enzimáticos/farmacologia , Proteína 2 Glutamina gama-Glutamiltransferase/antagonistas & inibidores , Rigidez Vascular/efeitos dos fármacos , Actinas/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiologia , Células Cultivadas , Colágeno/metabolismo , Elasticidade , Feminino , Humanos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Análise de Onda de PulsoRESUMO
OBJECTIVE: Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. METHODS: Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mgâ¢kg-1â¢day-1; ZOSV); Group 3: valsartan (31 mgâ¢kg-1â¢day-1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mgâ¢kg-1â¢day-1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. CONCLUSIONS: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.
Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Cardiomiopatias Diabéticas/prevenção & controle , Obesidade/tratamento farmacológico , Inibidores de Proteases/farmacologia , Valsartana/farmacologia , Rigidez Vascular/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole , Modelos Animais de Doenças , Combinação de Medicamentos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Neprilisina/antagonistas & inibidores , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Ratos Zucker , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Polyploidy or whole-genome duplication (WGD) is widespread in plants and is a key driver of evolution and speciation, accompanied by rapid and dynamic changes in genomic structure and gene expression. The 3D structure of the genome is intricately linked to gene expression, but its role in transcription regulation following polyploidy and domestication remains unclear. Here, we generated high-resolution (â¼2 kb) Hi-C maps for cultivated soybean (Glycine max), wild soybean (Glycine soja), and common bean (Phaseolus vulgaris). We found polyploidization in soybean may induce architecture changes of topologically associating domains and subsequent diploidization led to chromatin topology alteration around chromosome-rearrangement sites. Compared with single-copy and small-scale duplicated genes, WGD genes displayed more long-range chromosomal interactions and were coupled with higher levels of gene expression and chromatin accessibilities but void of DNA methylation. Interestingly, chromatin loop reorganization was involved in expression divergence of the genes during soybean domestication. Genes with chromatin loops were under stronger artificial selection than genes without loops. These findings provide insights into the roles of dynamic chromatin structures on gene expression during polyploidization, diploidization, and domestication of soybean.
Assuntos
Cromatina/química , Domesticação , Regulação da Expressão Gênica de Plantas , Glycine max/genética , Poliploidia , Cromossomos de Plantas/genética , Diploide , Duplicação Gênica , Genoma de Planta , Phaseolus/genética , Glycine max/anatomia & histologiaRESUMO
Bread wheat (Triticum aestivum) is an allohexaploid that was formed via two allopolyploidization events. Growing evidence suggests histone modifications are involved in the response to 'genomic shock' and environmental adaptation during polyploid formation and evolution. However, the role of histone modifications, especially histone H3 lysine-27 dimethylation (H3K27me2), in genome evolution remains elusive. Here we analyzed H3K27me2 and H3K27me3 profiles in hexaploid wheat and its tetraploid and diploid relatives. Although H3K27me3 levels were relatively stable among wheat species with different ploidy levels, H3K27me2 intensities increased concurrent with increased ploidy levels, and H3K27me2 peaks were colocalized with massively amplified DTC transposons (CACTA family) in euchromatin, which may silence euchromatic transposons to maintain genome stability during polyploid wheat evolution. Consistently, the distribution of H3K27me2 is mutually exclusive with another repressive histone mark, H3K9me2, that mainly silences transposons in heterochromatic regions. Remarkably, the regions with low H3K27me2 levels (named H3K27me2 valleys) were associated with the formation of DNA double-strand breaks in genomes of wheat, maize (Zea mays) and Arabidopsis. Our results provide a comprehensive view of H3K27me2 and H3K27me3 distributions during wheat evolution, which support roles for H3K27me2 in silencing euchromatic transposons to maintain genome stability and in modifying genetic recombination landscapes. These genomic insights may empower breeding improvement of crops.
Assuntos
Instabilidade Genômica , Histonas/metabolismo , Poliploidia , Triticum/genética , Sequenciamento de Cromatina por Imunoprecipitação , Cromossomos de Plantas/genética , Elementos de DNA Transponíveis , Evolução Molecular , Genoma de Planta , Histonas/genética , Lisina/metabolismo , Recombinação Genética , Triticum/metabolismoRESUMO
BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.
Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/farmacologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Rigidez Vascular/efeitos dos fármacos , Albuminúria/etiologia , Albuminúria/prevenção & controle , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Glicosúria/etiologia , Glicosúria/prevenção & controle , Humanos , Rim/metabolismo , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fluxo Pulsátil/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVE: Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. MATERIALS/METHODS: Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. RESULTS: XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. CONCLUSIONS: Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration.
Assuntos
Dieta Ocidental , Inflamação/induzido quimicamente , Proteinúria/induzido quimicamente , Ácido Úrico/sangue , Rigidez Vascular/efeitos dos fármacos , Alopurinol/administração & dosagem , Alopurinol/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Úrico/farmacologia , Xantina Oxidase/antagonistas & inibidoresRESUMO
Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.
Assuntos
Alopurinol/administração & dosagem , Aorta/fisiologia , Dieta Ocidental , Ácido Úrico/sangue , Rigidez Vascular/fisiologia , Vasodilatação/fisiologia , Xantina Oxidase/metabolismo , Animais , Aorta/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologia , Xantina Oxidase/antagonistas & inibidoresRESUMO
Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.
Assuntos
Dieta Ocidental , Células Endoteliais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Rigidez Vascular/fisiologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Caderinas/genética , Caderinas/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Artéria Femoral/fisiologia , Immunoblotting , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Força Atômica , Análise de Onda de Pulso , Fator de Crescimento Transformador beta/metabolismo , Rigidez Vascular/genética , VasodilataçãoRESUMO
The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of Western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent Western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness, and impaired diastolic relaxation by reducing growth and profibrotic signaling pathways. Four-weeks-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125 mg/L), a xanthine oxidase inhibitor, for 16 weeks. The Western diet-induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally related to increases in body weight, fat mass, and insulin resistance without changes in blood pressure. The Western diet induced cardiomyocte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired diastolic relaxation. Further, the Western diet enhanced activation of the S6 kinase-1 growth pathway and the profibrotic transforming growth factor-ß1/Smad2/3 signaling pathway and macrophage proinflammatory polarization. All results improved with allopurinol treatment, which lowered cardiac xanthine oxidase as well as serum uric acid levels. These findings support the notion that increased production of uric acid with intake of a Western diet promotes cardiomyocyte hypertrophy, inflammation, and oxidative stress that lead to myocardial fibrosis and associated impaired diastolic relaxation.
Assuntos
Dieta Ocidental/efeitos adversos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Ácido Úrico/sangue , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Alopurinol/farmacologia , Animais , Biomarcadores/sangue , Gorduras na Dieta/efeitos adversos , Sacarose Alimentar/efeitos adversos , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/enzimologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Disfunção Ventricular Esquerda/sangue , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/efeitos dos fármacos , Xantina Oxidase/metabolismoRESUMO
The prevalence of obesity and associated medical disorders has increased dramatically in the United States and throughout much of the world in the past decade. Obesity, induced by excess intake of carbohydrates and fats, is a major cause of Type 2 diabetes, hypertension, and the cardiorenal metabolic syndrome. There is emerging evidence that excessive nutrient intake promotes signaling through the mammalian target of rapamycin (mTOR), which, in turn, may lead to alterations of cellular metabolic signaling leading to insulin resistance and obesity-related diseases, such as diabetes, cardiovascular and kidney disease, as well as cancer. While the pivotal role of mTOR signaling in regulating metabolic stress, autophagy, and adaptive immune responses has received increasing attention, there remain many gaps in our knowledge regarding this important nutrient sensor. For example, the precise cellular signaling mechanisms linking excessive nutrient intake and enhanced mTOR signaling with increased cardiovascular and kidney disease, as well as cancer, are not well understood. In this review, we focus on the effects that the interaction between excess intake of nutrients and enhanced mTOR signaling have on the promotion of obesity-associated diseases and potential therapeutic strategies involving targeting mTOR signaling.
Assuntos
Doenças Cardiovasculares/etiologia , Obesidade/complicações , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Ingestão de Energia , Metabolismo Energético , Humanos , Resistência à Insulina , Terapia de Alvo Molecular , Obesidade/tratamento farmacológico , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo , Fatores de Risco , Transdução de Sinais/efeitos dos fármacosRESUMO
The cardiorenal metabolic syndrome (CRS) consists of a constellation of cardiac, renal, and metabolic disorders including insulin resistance (IR), obesity, metabolic dyslipidemia, high-blood pressure, and evidence of early cardiac and renal disease. Mitochondria dysfunction often occurs in the CRS, and this dysfunction is promoted by excess reactive oxygen species, genetic factors, IR, aging, and altered mitochondrial biogenesis. Recently, it has been shown that there are important sex-related differences in mitochondria function and metabolic, cardiovascular, and renal components. Sex differences in the CRS have mainly been attributed to the estrogen's effects that are mainly mediated by estrogen receptor (ER) α, ERß, and G-protein coupled receptor 30. In this review, we discuss the effects of estrogen on the mitochondrial function, insulin metabolic signaling, glucose transport, lipid metabolism, and inflammatory responses from liver, pancreatic ß cells, adipocytes, skeletal muscle, and cardiovascular tissue.
Assuntos
Estrogênios/metabolismo , Rim/patologia , Síndrome Metabólica/metabolismo , Mitocôndrias/metabolismo , Miocárdio/patologia , Animais , Humanos , Rim/metabolismo , Síndrome Metabólica/patologia , Miocárdio/metabolismo , Transdução de SinaisRESUMO
Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.
Assuntos
Sistema Cardiovascular/imunologia , Inflamação/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Obesidade/imunologia , Sistema Renina-Angiotensina/imunologia , Imunidade Adaptativa , Animais , Síndrome Cardiorrenal/imunologia , Diabetes Mellitus/imunologia , Progressão da Doença , Humanos , Hipertensão Renal/imunologia , Insulina/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Pré-Menopausa , Receptor de Insulina/metabolismo , Comportamento Sedentário , Fatores Sexuais , Linfócitos T Reguladores/imunologiaRESUMO
Vascular calcification predicts an increased risk for cardiovascular events in atherosclerosis, diabetes, and end-stage kidney diseases. Matrix Gla protein (MGP), an inhibitor of calcification, limits calcium phosphate deposition in the vessel wall. There are many factors contributing to the progression of atherosclerosis, including hypertension, hyperlipidemia, the renin-angiotensin system, and inflammation. Angiotensin II (ANG II) plays a crucial role in the atherogenic process through not only its pressor responses but also its growth-promoting and inflammatory effects. In this study, we investigated the role of MGP in ANG II-induced exacerbation of vascular calcification in human vascular smooth muscle cells (VSMCs). The expression of MGP, calcification, and apoptosis in human VSMCs were examined by Western blot analysis, real-time PCR, in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and enzyme-linked immunosorbent assay, respectively. Increase in VSMC calcification in human atherosclerotic plaques upregulates MGP expression and apoptosis in a negative feedback manner. ANG II inhibited MGP expression in VSMCs via and in vitro in a dose- and time-dependent manner through ANG II type 1 receptor and NF-κB signaling pathway. Meanwhile, MGP inhibited the calcification, caspase-3 activity, activation of runt-related transcription factor 2, and release of inflammatory cytokines by VSMCs induced by calcification medium (2.5 mM P(i)) and ANG II in vitro. These observations provide evidence that ANG II exacerbates vascular calcification through activation of the transcription factors, runt-related transcription factor 2 and NF-κB, and regulation of MGP, inflammatory cytokines expression in human VSMCs.
Assuntos
Angiotensina II/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Doenças das Artérias Carótidas/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Calcificação Vascular/metabolismo , Idoso , Apoptose , Western Blotting , Fosfatos de Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/patologia , Caspase 3/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Citocinas/metabolismo , Ativação Enzimática , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/genética , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Humanos , Marcação In Situ das Extremidades Cortadas , Mediadores da Inflamação/metabolismo , Pessoa de Meia-Idade , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Placa Aterosclerótica , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Calcificação Vascular/genética , Calcificação Vascular/imunologia , Calcificação Vascular/patologia , Proteína de Matriz GlaRESUMO
Apoptosis of vascular smooth muscle cells (SMCs) is controlled by a balance between the effect of growth factors and cytokines, and is involved in plaque instability in advanced atherosclerotic lesions. Recently, we reported high levels of atheroma-associated cytokines, including tumor necrosis factor-α (TNF-α), in carotid plaques of symptomatic patients. These cytokines induce apoptosis of vascular SMCs, and thus could be responsible for plaque rupture, a clinically devastating event. In this study, we examined the effect of TNF-α on the cell cycle inhibitor p27(kip) and apoptosis of SMCs in human carotid plaques, and the underlying mechanism. Both Forkhead box subclass o1 (FoxO1) and p27(kip) were more strongly expressed in symptomatic than asymptomatic atherosclerotic plaques. TNF-α significantly induced the expression of FoxO1 in asymptomatic plaque SMCs in a dose- and time-dependent manner via JNK signaling pathway. TNF-α also induced phosphorylation of FoxO1, resulting in its cytoplasmic translocation/nuclear exclusion of transcription factors. The effect of TNF-α was blocked by the PI3K inhibitor, LY294002. Meanwhile, TNF-α not only induced the p27(kip) expression and cell cycle arrest in the G(0)-G(1) phase, but also enhanced caspase-3 activity and induced apoptosis in SMCs of asymptomatic plaques. However, the potential effect of TNF-α on the cell cycle inhibitor p27(kip) and apoptosis of SMCs was inhibited by siRNA against FoxO1 in asymptomatic patients. These data suggest the involvement of FoxO1 transcription factor in TNF-α-induced expression of a cell cycle regulatory protein and apoptosis of SMCs, thus regulating the stability of atherosclerotic plaques with carotid stenosis.