RESUMO
The process of aging is characterized by structural degeneration and functional decline, as well as diminished adaptability and resistance. The aging kidney exhibits a variety of structural and functional impairments. In aging mice, thinning and graying of fur were observed, along with a significant increase in kidney indices compared to young mice. Biochemical indicators revealed elevated levels of creatinine, urea nitrogen and serum uric acid, suggesting impaired kidney function. Histological analysis unveiled glomerular enlargement and sclerosis, severe hyaline degeneration, capillary occlusion, lymphocyte infiltration, tubular and glomerular fibrosis, and increased collagen deposition. Observations under electron microscopy showed thickened basement membranes, altered foot processes, and increased mesangium and mesangial matrix. Molecular marker analysis indicated upregulation of aging-related ß-galactosidase, p16-INK4A, and the DNA damage marker γH2AX in the kidneys of aged mice. In metabolomics, a total of 62 significantly different metabolites were identified, and 10 pathways were enriched. We propose that citrulline, dopamine, and indoxyl sulfate have the potential to serve as markers of kidney damage related to aging in the future. Phosphoproteomics analysis identified 6656 phosphosites across 1555 proteins, annotated to 62 pathways, and indicated increased phosphorylation at the Ser27 site of Minichromosome maintenance complex component 2 (Mcm2) and decreased at the Ser284 site of heterogeneous nuclear ribonucleoprotein K (hnRNP K), with these modifications being confirmed by western blotting. The phosphorylation changes in these molecules may contribute to aging by affecting genome stability. Eleven common pathways were detected in both omics, including arginine biosynthesis, purine metabolism and biosynthesis of unsaturated fatty acids, etc., which are closely associated with aging and renal insufficiency.
Assuntos
Envelhecimento , Instabilidade Genômica , Rim , Componente 2 do Complexo de Manutenção de Minicromossomo , Animais , Envelhecimento/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Instabilidade Genômica/genética , Camundongos , Fosforilação , Rim/metabolismo , Rim/patologia , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Camundongos Endogâmicos C57BL , Masculino , Metabolômica/métodos , Dano ao DNA , MultiômicaRESUMO
Aging is widely accepted as an independent risk factor for cardiovascular disease (CVD), which contributes to increasing morbidity and mortality in the elderly population. Lysine ß-hydroxybutyrylation (Kbhb) is a novel post-translational modification (PTM), wherein ß-hydroxybutyrate is covalently attached to lysine ε-amino groups. Recent studies have revealed that histone Kbhb contributes to tumor progression, diabetic cardiomyopathy progression, and postnatal heart development. However, no studies have yet reported a global analysis of Kbhb proteins in aging hearts or elucidated the mechanisms underlying this modification in the process. Herein, we conducted quantitative proteomics and Kbhb PTM omics to comprehensively elucidate the alterations of global proteome and Kbhb modification in the hearts of aged mice. The results revealed a decline in grip strength and cardiac diastolic function in 22-month-old aged mice compared to 3-month-old young mice. High-throughput liquid chromatogram-mass spectrometry analysis identified 1710 ß-hydroxybutyrylated lysine sites in 641 proteins in the cardiac tissue of young and aged mice. Additionally, 183 Kbhb sites identified in 134 proteins exhibited significant differential modification in aged hearts (fold change (FC) > 1.5 or <1/1.5, p < 0.05). Notably, the Kbhb-modified proteins were primarily detected in energy metabolism pathways, such as fatty acid elongation, glyoxylate and dicarboxylate metabolism, tricarboxylic acid cycle, and oxidative phosphorylation. Furthermore, these Kbhb-modified proteins were predominantly localized in the mitochondria. The present study, for the first time, provides a global proteomic profile and Kbhb modification landscape of cardiomyocytes in aged hearts. These findings put forth novel possibilities for treating cardiac aging and aging-related CVDs by reversing abnormal Kbhb modifications.
Assuntos
Lisina , Proteômica , Humanos , Idoso , Camundongos , Animais , Lactente , Lisina/metabolismo , Proteômica/métodos , Histonas/metabolismo , Envelhecimento/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
AMP-activated protein kinase alpha 2 (AMPKα2) regulates energy metabolism, protein synthesis, and glucolipid metabolism myocardial cells. Ketone bodies produced by fatty acid ß-oxidation, especially ß-hydroxybutyrate, are fatty energy-supplying substances for the heart, brain, and other organs during fasting and long-term exercise. They also regulate metabolic signaling for multiple cellular functions. Lysine ß-hydroxybutyrylation (Kbhb) is a ß-hydroxybutyrate-mediated protein posttranslational modification. Histone Kbhb has been identified in yeast, mouse, and human cells. However, whether AMPK regulates protein Kbhb is yet unclear. Hence, the present study explored the changes in proteomics and Kbhb modification omics in the hearts of AMPKα2 knockout mice using a comprehensive quantitative proteomic analysis. Based on mass spectrometry (LC-MS/MS) analysis, the number of 1181 Kbhb modified sites in 455 proteins were quantified between AMPKα2 knockout mice and wildtype mice; 244 Kbhb sites in 142 proteins decreased or increased after AMPKα2 knockout (fold change >1.5 or <1/1.5, p < 0.05). The regulation of Kbhb sites in 26 key enzymes of fatty acid degradation and tricarboxylic acid cycle was noted in AMPKα2 knockout mouse cardiomyocytes. These findings, for the first time, identified proteomic features and Kbhb modification of cardiomyocytes after AMPKα2 knockout, suggesting that AMPKα2 regulates energy metabolism by modifying protein Kbhb.
Assuntos
Ácido 3-Hidroxibutírico , Proteínas Quinases Ativadas por AMP , Miocárdio , Animais , Humanos , Camundongos , Ácido 3-Hidroxibutírico/química , Ácido 3-Hidroxibutírico/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Cromatografia Líquida , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Proteômica , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Aging is characterized by a general decline in cellular function, which ultimately affects whole body homeostasis. This study aimed to investigate the effects and underlying mechanisms of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) on the livers of naturally aging mice. METHOD: Twenty-two-month-old C57BL6 mice were used as a natural aging animal model, divided into a saline-treated wild-type aged control group (WT-AC) and a hUCMSC-exo-treated group (WT-AEX), and then detected by morphology, metabolomics and phosphoproteomics. RESULTS: Morphological analysis showed that hUCMSC-exos ameliorated structural disorder and decreased markers of senescence and genome instability in aging livers. Metabolomics showed that hUCMSC-exos decreased the contents of saturated glycerophospholipids, palmitoyl-glycerols and eicosanoid derivatives associated with lipotoxicity and inflammation, consistent with the decreased phosphorylation of metabolic enzymes, such as propionate-CoA ligase (Acss2), at S267 detected by phosphoproteomics. Moreover, phosphoproteomics indicated that hUCMSC-exos reduced the phosphorylation of proteins participating in nuclear transport and cancer signaling, such as heat shock protein HSP90-beta (Hsp90ab1) at S226 and nucleoprotein TPR (Tpr) at S453 and S379, while increasing those involved in intracellular communication, such as calnexin (Canx) at S563 and PDZ domain-containing protein 8 (Pdzd8). Finally, phosphorylated HSP90ß and Tpr were verified predominantly in hepatocytes. CONCLUSION: HUCMSC-exos improved metabolic reprogramming and genome stability mainly associated with phosphorylated HSP90ß in hepatocytes in natural aging livers. This work provides a comprehensive resource of biological data by omics to support future investigations of hUCMSC-exos in aging.
Assuntos
Exossomos , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Idoso , Lactente , Exossomos/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Envelhecimento , Células-Tronco Mesenquimais/metabolismo , Metabolômica , Cordão Umbilical , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Clostridium ghonii (C. ghonii) is a non-pathogenic Clostridium species and a strictly anaerobic, spore-forming bacterium. However, its bacterial oncolytic capabilities and applications have not yet been reported. This study aimed to determining the bacterial oncolytic capability of C. ghonii for the treatment of experimental solid tumors. C. ghonii secreted collagenase IV and phospholipase c and significantly promoted apoptosis and necrosis in cultured A549 cells. C. ghonii spores specially germinated and were distributed in the tumors, and elicited the immune responses after intratumoral injection in tumor-bearing mice. C. ghonii spores decreased tumor volumes and increased tumor necrosis and inhibition rates in tumor-bearing mice. Furthermore, the combination of radiation and C. ghonii exerted additive anti-tumor effects. Taken together, our data indicate that C. ghonii is a bacteriolytic therapeutic agent against solid tumors. Given the proven natural safety of C. ghonii, it is attractive as a potential novel bacteriolytic therapy for solid tumors.
Assuntos
Neoplasias Experimentais , Neoplasias , Camundongos , Animais , Esporos Bacterianos , Clostridium , Neoplasias/patologia , Neoplasias Experimentais/terapia , NecroseRESUMO
OBJECTIVES: Although injury of myocardium after percutaneous coronary intervention (PCI) has been reported, the mechanism and effect of exogenous phosphocreatine (PCr) supplementation on the injury are yet to be elucidated. Biomarkers, such as interleukin-6 (IL-6) and variations in white blood cells for inflammation, and serum cardiac troponin I (cTnI) for myocardial injury are examined. METHODS: A total of 105 patients undergoing PCI were included and randomly divided into two groups: control (treated with routine hydration therapy) and PCr (treated with additional intravenous infusion of exogenous PCr). The serum levels of biomarkers were detected at administration and 4, 12, 24, and 48 h after PCI, with natural logarithmic (loge) transformation of data when modeling assumptions were not fulfilled. RESULTS: The level of loge-transformed IL-6 increased in both groups, especially at 12 and 24 h after the operation, and that of PCr group was less than the control group at 48 h. The content of loge-transformed cTnI was significantly increased in both groups, while that of the PCr group was markedly lower than the control group at all time points after PCI. Moreover, the ratio of neutrophils was elevated at all time points after PCI, while that of the PCr group was lower at 48 h, and the variations in the ratio of lymphocytes showed opposite results. CONCLUSIONS: Exogenous phosphocreatine reduces stent implantation, triggers inflammation manifested as decreased serum levels of IL-6 and the aggregation of neutrophils, and protects the myocardium of the patients undergoing PCI. These findings provided the potential mechanism and treatment for myocardial injury associated with PCI.
Assuntos
Inflamação , Intervenção Coronária Percutânea , Fosfocreatina , Biomarcadores , Humanos , Inflamação/prevenção & controle , Interleucina-6 , Miocárdio , Intervenção Coronária Percutânea/efeitos adversos , Fosfocreatina/uso terapêutico , Troponina IRESUMO
Diabetic cardiovascular complication is a common systemic disease with high morbidity and mortality worldwide. We hypothesise that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs-exos) can rescue these disorders and alleviate vascular remodeling in diabetes. Morphological, non-targeted metabolomics and 4D label-free proteomics techniques were used to analyze the aortas of db/m mice as normal control group (NCA), saline treated db/db mice (DMA), and hUCMSCs-exos treated db/db mice (DMTA), and to clarify the molecular mechanism of the protection of hUCMSCs-exos in vascular remodeling from a new point of view. The results showed that 74 metabolites were changed significantly in diabetic aortas, of which 15 were almost restored by hUCMSCs-exos. In proteomics, 30 potential targets such as Stromal cell-derived factor 2-like protein 1, Leukemia inhibitory factor receptor, Peroxisomal membrane protein and E3 ubiquitin-protein ligase MYCBP2 were detected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based analysis showed that Central carbon metabolism in cancer and Galactose metabolism pathway were up-regulated to near normal by hUCMSCs-exos in metabolomics, with janus associated kinase-signal transducer and activator of transcription (JAK-STAT) pathway displayed in proteomics. According to bioinformatics and integrated analysis, these targeted molecules of hUCMSCs-exos to attenuate the vascular remodeling were mainly associated with regulation of energy metabolism, oxidative stress, inflammation, and cellular communications. This study provided a reference for the therapy of diabetes-induced cardiovascular complications.
Assuntos
Exossomos , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Exossomos/metabolismo , Cordão Umbilical , Proteômica , Remodelação Vascular , Células-Tronco Mesenquimais/metabolismo , AortaRESUMO
Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of L-carnitine, an inhibitor of the JNK/p53 pathway in adipose tissue SASP and dysfunction. Young and aging rat were given L-carnitine by gavage. Next, we detected the senescence, cytokines expression, chronic inflammation and insulin resistance of adipose tissue. Additionally, JNK/p53 pathway was estimated. Our results show a significant increase expression of SASP components in the adipose tissue of aging rats compared to young rats. Further, we found that infiltration of immune cells and the expression of pro-inflammatory cytokines were enhanced in aging adipose tissue while insulin signaling activity was reduced in aging adipose tissue. Interestingly, L-carnitine markedly reduced the expression of SASP factors. L-Carnitine could significantly reduce chronic inflammation, improving insulin resistance. Further, L-carnitine inhibited SASP by inhibiting JNK/p53 pathway. L-Carnitine inhibited SASP by JNK/p53 pathway and attenuated adipose tissue dysfunction of aging.
Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/fisiologia , Carnitina , Senescência Celular , Animais , Carnitina/metabolismo , Carnitina/farmacologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Lidocaine, a common local anesthetic drug, has anti-inflammatory effects. It has demonstrated a protective effect in mice from septic peritonitis. However, it is unknown whether lidocaine has effects on high mobility group box 1 (HMGB1), a key mediator of inflammation. In this study, we investigated the effect of lidocaine treatment on serum HMGB1 level and HMGB1 expression in liver, lungs, kidneys, and ileum in septic rats induced by cecal ligation and puncture (CLP). We found that acute organ injury induced by CLP was mitigated by lidocaine treatment and organ function was significantly improved. The data also demonstrated that lidocaine treatment raised the survival of septic rats. Furthermore, lidocaine suppressed the level of serum HMGB1, the expression of HMGB1, and the activation of NF-κB p65 in liver, kidneys, lungs, and ileum. Taken together, these results suggest that lidocaine treatment exerts its protective effection on CLP-induced septic rats. The mechanism was relative to the inhibitory effect of lidocaine on the mRNA expression level of HMGB1 in multiple organs, release of HMGB1 to plasma, and activation of NF- κB.
Assuntos
Proteína HMGB1/antagonistas & inibidores , Lidocaína/uso terapêutico , NF-kappa B/fisiologia , Sepse/tratamento farmacológico , Animais , Proteína HMGB1/sangue , Proteína HMGB1/genética , Lidocaína/farmacologia , Masculino , Peroxidase/metabolismo , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/análise , Ratos , Ratos Wistar , Sepse/mortalidadeRESUMO
Accurate modeling of Gross Primary Productivity (GPP) in terrestrial ecosystems is a major challenge in quantifying the carbon cycle. Many light use efficiency (LUE) models have been developed, but the variables and algorithms used for environmental constraints in different models vary importantly. It is still unclear whether the models can be further improved by machine learning methods and the combination of different variables. Here, we have developed a series of RFR-LUE models, which used the random forest regression (RFR) algorithm based on variables of LUE models, to explore the potential of estimating site-level GPP. Based on remote sensing indices, eddy covariance and meteorological data, we applied RFR-LUE models to evaluate the effects of different variables combined on GPP on daily, 8-day, 16-day and monthly scales, respectively. Cross-validation analyses revealed performances of RFR-LUE models varied significantly among sites with R2 of 0.52-0.97. Slopes of the regression relationship between simulated and observed GPP ranged from 0.59 to 0.95. Most models performed better in capturing the temporal changes and magnitude of GPP in mixed forests and evergreen needle-leaf forests than in evergreen broadleaf forests and grasslands. Performances were improved at the longer temporal scale, with the average R2 for four-time resolutions of 0.81, 0.87, 0.88, and 0.90, respectively. Additionally, the importance of the variables showed that temperature and vegetation indices were critical variables for RFR-LUE models, followed by radiation and moisture variables. The importance of moisture variables was higher in non-forests than in forests. A comparison with four GPP products indicated that RFR-LUE model predicted GPP better matcher observed GPP across sites. The study provided an approach to deriving GPP fluxes and evaluating the extent to which variables affect GPP estimation. It may be used for predicting vegetation GPP at the regional scales and for calibration and evaluation of land surface process models.
RESUMO
Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism. Analysis showed that the body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the WTA group. The grips decreased with age, while the triglyceride (TG) and cholesterol (TC) did not change significantly. The increase of fibrosis, accumulation of inflammatory cells, hepatocytes degeneration, the deposition of lipid droplets and glycogen, the damaged mitochondria, and deduction of endoplasmic reticulum were observed in the aging liver under optical and electron microscopes. In addition, a network of metabolites and phosphorylated proteomes of the aging liver was established. Metabolomics detected 970 metabolites in the positive ion mode and 778 metabolites in the negative ion mode. A total of 150 pathways were pooled. Phosphoproteomics identified 2618 proteins which contained 16621 phosphosites. A total of 164 pathways were detected. 65 common pathways were detected in two omics. Phosphorylated protein heat shock protein HSP 90-alpha (HSP90A) and v-raf murine viral oncogene homolog B1(BRAF), related to cancer pathway, were significantly upregulated in aged mice liver. Western blot verified that protein expression of MEK and ERK, downstream of BRAF pathway were elevated in the liver of aging mice. However, the protein expression of BRAF was not a significant difference. Overall, these findings revealed a close link between aging and cancer and contributed to our understanding of the multi-omics changes in natural aging.
RESUMO
To improve the application of endophyte Bacillus velezensis BY6 from the xylem of poplar, the effect of BY6 on the growth of diseased Populus davidiana × Populus. alba var. pyramidalis Louche (Pdpap poplar) seedlings and the biological control effect on the pathogen Armillaria solidipes were tested using a plant split-root experiment. After applying BY6 to the roots of diseased Pdpap poplar seedlings, the results show that plant growth indicators (dry mass, fresh mass, and plant height) were significantly increased (p < 0.05), and genes related to auxin hormone signal transcription were activated. BY6 indicated a surprising control effect after the inoculation of diseased Pdpap poplar seedlings. Compared to the infected control group, the treated disease index of the diseased Pdpap poplar seedlings in the treatment group were reduced by 49.53% on the 20th day. The relative staining areas of diaminobenzidine (DAB) and Trypan blue decreased by 3.37 and 7.31 times, respectively. The physiological indicators (soluble sugar and protein) and oxidase indicators were significantly increased (p < 0.05). The expression levels of defense genes related to salicylic acid (SA) and jasmonic acid (JA) signaling pathways were significantly increased (p < 0.05). Amazingly, the results indicate that BY6 simultaneously activates induced systemic resistance (ISR) and systemic acquired resistance (SAR) in diseased Pdpap poplar seedlings and promotes growth. The results indicate that BY6 is a promising candidate for developing forest tree biofertilizers and biopesticides.
RESUMO
Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy. Methods:In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations. Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.
Assuntos
Angiotensina II/análogos & derivados , Cardiomiopatias Diabéticas/fisiopatologia , Proteína Forkhead Box O1/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Angiotensina II/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Glicemia , Linhagem Celular , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Fibrose/fisiopatologia , Proteína Forkhead Box O1/fisiologia , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quinolonas/farmacologia , Transdução de Sinais , Estreptozocina/farmacologia , Disfunção Ventricular EsquerdaRESUMO
BACKGROUND: This study aimed to investigate the effects of trimetazidine and lcarnitine on heart aging and cardiac metabolism in the natural aging rats and explore the possible mechanism regarding the regulation of cardiac metabolic substrates. METHODS: A total of 28 young (2-month-old) and 28 aged (14-month-old) male Sprague-Dawley rats were randomly allocated to the following groups: young control (YC, nâ¯=â¯8), young trimetazidine (YT, nâ¯=â¯10), young lcarnitine (YL, nâ¯=â¯10), aging control (AC, nâ¯=â¯8), aging trimetazidine (AT, nâ¯=â¯10), and aging lcarnitine (AL, nâ¯=â¯10). All rats were intragastrically treated with saline, trimetazidine, or lcarnitine for 4â¯weeks. Blood sample parameters (MDA, SOD, Glu, TG, TC, LDL-c, HDL-c, AST, ALT, ALP, BUN, Cr, LDH), Echocardiographic paramerters, ATP levels of cardiac apex, cardiac pathology (HE staining and mitochondrial ultrastructures), and cardiac metabolism-related parameters (glucose transporter type-4[GLUT-4], carnitine palmitoyl transferase1[CPT-1]) were analyzed in each group. RESULTS: The left ventricular ejection fractions were normal in most groups, with a higher value observed in the AT group than in the AC group. The AC group showed decreased ATP levels of cardiac apex compared with the YC group. But both trimetazidine and lcarnitine attenuated the aging-induced decrease in ATP levels of cardiac apex. The AC group also showed increased myocardial fiber fragmentations and dissolutions, and interstitial proliferation compared with the YC group. However both trimetazidine and lcarnitine protected against the aging-induced pathological changes in myocardium. Furthermore, both trimetazidine and lcarnitine prevented mitochondria of cardiomyocytes from aging-induced injury. Both the AT and AL groups had significantly fewer focal cavitations and higher mitochondrial matrix electron densities than the AC group. GLUT-4 and CPT-1 protein levels were significantly lower while GLUT-4/CPT-1 ratios were higher in aging rats than YC rats. The AT and AL groups had significantly higher GLUT-4 and CPT-1 levels than the AC group, with more significant changes observed in the AT group. CONCLUSIONS: Trimetazidine and lcarnitine may partially improve the age-related changes of rat myocardial metabolisms and heart function via regulating cardiac metabolic substrates, with trimetazidine being superior. Interestingly, they may also reduce cardiac energy generation and impair mitochondrial structures in young rats. These findings suggest that age should be taken as an independent factor during the use of metabolic modulatory drugs in the patients with cardiovascular diseases because it may completely change the effects of drugs.
Assuntos
Envelhecimento , Carnitina/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Trimetazidina/farmacologia , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Ecocardiografia , Transportador de Glucose Tipo 4/metabolismo , Masculino , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
GP IIb/IIIa receptor activation plays an important role in thrombosis. The mechanism of early activation of GP IIb/IIIa receptors in diabetic conditions remains unknown. The purpose of this study was to investigate the release of Endothelial microparticle (EMP)-associated protein disulfide isomerase (PDI) after endothelial cell injury induced in diabetes and the changes in platelet activation. We produced an animal model of type 2 diabetes mellitus using ApoE-/- mice. Normal ApoE-/- and diabetic mice were allocated to four groups (n = 15): normal diet, normal diet plus rutin, diabetic, and diabetes plus rutin. The EMP-PDI content and GP IIb/IIIa expression of mice platelets were determined. In addition, EMPs obtained from the four groups were pretreated with the PDI inhibitor rutin; then, their effects on the platelets of normal C57 mice were characterized. Compared with the normal diet group, the diabetic group had significantly increased plasma EMP-PDI content and accelerated platelet activation by increased GP IIb/IIIa expression. In conclusion, EMP-PDI promotes early platelet activation through glycoprotein (GP) IIb/IIIa receptors present on platelet surface in the diabetic state. However, this process could be partially suppressed by the administration of rutin.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Rutina/farmacologiaRESUMO
BACKGROUND Diabetic cardiomyopathy (DCM) is a common but underestimated cause of heart failure in patients with diabetes. This study investigated the myocardial-protective effects of nicorandil (Nic) on rats with DCM. MATERIAL AND METHODS A total of forty-seven 180-220 g male Wistar rats were randomly divided into 4 groups: a control group (control, n=8), a DCM group (DCM, n=13), a nicorandil-pretreated DCM group (Nic1, n=13), and a nicorandil-treated DCM group (Nic2, n=13). A rat model of type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin (STZ). Nicorandil (3 mg/kg/d) was orally administrated to rats in the Nic1 group starting at week 4. Nicorandil (3 mg/kg/d) was orally administrated only after the induction of diabetes in the Nic2 group. The serum lipoids, plasma glucose, insulin levels, heart weight index, serum creatine kinase (CK), lactate dehydrogenase (LDH) levels, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) were analyzed in all groups. RESULTS The DCM group showed increased heart weight index, serum LDH, CK, and MDA content and decreased serum SOD activity, as compared with the control group (P<0.05). The DCM-induced increases in heart weight index, serum LDH, CK, and MDA content and decrease in serum SOD activity were attenuated in both Nic1 and Nic2 groups (P<0.05). However, there was no significant difference between Nic1 and Nic2 groups (P>0.05). CONCLUSIONS Nicorandil has protective effects on cardiac hypertrophy in DCM rats through increased SOD activity and decreased MDA content. Therefore, nicorandil may be a therapeutic method for diabetic patients with DCM.
Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Nicorandil/farmacologia , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Miocárdio/metabolismo , Nicorandil/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Nicorandil, the first clinically applied ATP-sensitive K+ channel (K+ATP) opener with nitrate property, has demonstrated cardioprotective effects in patients with multiples of heart diseases. However, it is unknown whether nicorandil has effects on left ventricular (LV) remodeling in rats with ischemic heart failure and the potential mechanisms remain unclear. In this study, we investigated the effects of nicorandil on cardiac function, LV remodeling, and Bax expression in myocardium of LV in rats with ischemic heart failure. We found that nicorandil could improve not only the general condition, but also the cardiac function in rats with ischemic heart failure. The data also demonstrated that nicorandil reduced the hypertrophy and fibrosis of LV in rats with ischemic heart failure. Furthermore, nicorandil suppressed the protein level of Bax expression in LV myocardium. Taken together, these results suggest that nicorandil exerts its cardioprotective effect and improves LV remodeling in rats with ischemic heart failure. The mechanism might be relative to the inhibitory effect of nicorandil on the protein level of Bax expression in LV myocardium.
Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Nicorandil/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Masculino , Isquemia Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/biossínteseRESUMO
The association of single nucleotide polymorphisms rs1053239 and rs2479 of cell death-inducing DFFA-like effector c with the risk of metabolic syndrome and its components, and with the efficacy and cost-effectiveness of antihypertensive drugs was investigated. Totally 1064 subjects with metabolic syndrome and 1099 controls of Chinese Han nationality were recruited. Clinical assessment was conducted with medication records collected at baseline and during 5-year follow-up. Carriers of rs2479 A allele were at higher risk to develop elevated fasting glucose than non-carriers (P = 0.004). A allele at rs2479 were associated with a 5-year aggravation of blood triglyceride (P < 0.001) and diastolic blood pressure (P = 0.003), and C allele at rs1053239 with the exacerbation of systolic (P < 0.001) and diastolic blood pressure (P = 0.001). Moreover, efficacy and cost-effectiveness of angiotensin II-targeted drugs were higher in subjects with rs2479 A allele or rs1053239 C allele. These findings suggest that carriers of rs2479 A allele are predisposed to the development of increased fasting glucose, and the progressive elevation of blood triglyceride. Individuals with A allele at rs2479 or C allele at rs1053239 are more susceptible to a rapid progression of blood pressure, and benefit more from angiotensin II-targeted therapy.
Assuntos
Anti-Hipertensivos/uso terapêutico , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Adulto , Anti-Hipertensivos/farmacologia , Proteínas Reguladoras de Apoptose , Estudos de Casos e Controles , Análise Custo-Benefício , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Vigilância da População , Resultado do TratamentoRESUMO
BACKGROUND: Downregulation of peroxisome proliferator-activated receptor-alpha (PPARalpha) in hypertrophied and failing hearts leads to the reappearance of the fetal metabolic pattern, ie, decreased fatty acid oxidation and increased reliance on carbohydrates. Here, we sought to elucidate the functional significance of this shift in substrate preference. METHODS AND RESULTS: We assessed contractile function and substrate utilization using 13C nuclear magnetic resonance spectroscopy and high-energy phosphate metabolism using 31P nuclear magnetic resonance spectroscopy in perfused hearts isolated from genetically modified mice (PPARalpha(-/-)) that mimic the metabolic profile in myocardial hypertrophy. We found that the substrate switch from fatty acid to glucose (3-fold down) and lactate (3-fold up) in PPARalpha(-/-) hearts was sufficient for sustaining normal energy metabolism and contractile function at baseline but depleted the metabolic reserve for supporting high workload. Decreased ATP synthesis (measured by 31P magnetization transfer) during high workload challenge resulted in progressive depletion of high-energy phosphate content and failure to sustain high contractile performance. Interestingly, the metabolic and functional defects in PPARalpha(-/-) hearts could be corrected by overexpressing the insulin-independent glucose transporter GLUT1, which increased the capacity for glucose utilization beyond the intrinsic response to PPARalpha deficiency. CONCLUSIONS: These findings demonstrate that metabolic remodeling in hearts deficient in PPARalpha increases the susceptibility to functional deterioration during hemodynamic overload. Moreover, our results suggest that normalization of myocardial energetics by further enhancing myocardial glucose utilization is an effective strategy for preventing the progression of cardiac dysfunction in hearts with impaired PPARalpha activity such as hearts with pathological hypertrophy.
Assuntos
Glicemia/metabolismo , Cardiopatias/fisiopatologia , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , PPAR alfa/fisiologia , Animais , Modelos Animais de Doenças , Cardiopatias/genética , Camundongos , Camundongos Knockout , Contração Miocárdica/genética , PPAR alfa/deficiência , PPAR alfa/genéticaRESUMO
BACKGROUND: AMP-activated protein kinase (AMPK) regulatory gamma2 subunit (PRKAG2) mutations cause a human cardiomyopathy with cardiac hypertrophy, preexcitation, and glycogen deposition. PRKAG2 cardiomyopathy is recapitulated in transgenic mice overexpressing mutant PRKAG2 N488I in the heart (TGgamma2N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic (alpha) and 2 regulatory (beta and gamma) subunits. Two alpha-subunit isoforms, alpha1 and alpha2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative alpha2 subunit of AMPK (TGalpha2DN) provide a tool for selectively inhibiting alpha2, but not alpha1, subunit-associated AMPK activity. METHODS AND RESULTS: In compound-heterozygous TGgamma2N488I/TGalpha2DN mice, AMPK activity associated with alpha2 but not alpha1 was decreased compared with TGgamma2N488I. The TGalpha2DN transgene reduced the disease phenotype of TGgamma2N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TGgamma2N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TGgamma2N488I mice after exercise stress, indicating availability of the stored glycogen for metabolic utilization. No differences in glycogen-metabolizing enzymes were observed. CONCLUSIONS: The PRKAG2 N488I mutation causes inappropriate AMPK activation, which leads to glycogen accumulation and conduction system disease. The accumulated glycogen can serve as an energy source, and the animals have contractile reserve during exercise. Because the dominant-negative alpha2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the alpha2 rather than the alpha1 subunit are the primary mediators of the effects of PRKAG2 mutations.