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Diabetic cardiomyopathy (DCM) is a common severe complication of diabetes that occurs independently of hypertension, coronary artery disease, and valvular cardiomyopathy, eventually leading to heart failure. Previous studies have reported that Tectorigenin (TEC) possesses extensive anti-inflammatory and anti-oxidative stress properties. In this present study, the impact of TEC on diabetic cardiomyopathy was examined. The model of DCM in mice was established with the combination of a high-fat diet and STZ treatment. Remarkably, TEC treatment significantly attenuated cardiac fibrosis and improved cardiac dysfunction. Concurrently, TEC was also found to mitigate hyperglycemia and hyperlipidemia in the DCM mouse. At the molecular level, TEC is involved in the activation of AMPK, both in vitro and in vivo, by enhancing its phosphorylation. This is achieved through the regulation of endothelial-mesenchymal transition via the AMPK/TGFß/Smad3 pathway. Furthermore, it was demonstrated that the level of ubiquitination of the adiponectin receptor 1 (AdipoR1) protein is associated with TEC-mediated improvement of cardiac dysfunction in DCM mice. Notably the substantial reduction of myocardial fibrosis. In conclusion, TEC improves cardiac fibrosis in DCM mice by modulating the AdipoR1/AMPK signaling pathway. These findings suggest that TEC could be an effective therapeutic agent for the treatment of diabetic cardiomyopathy.
Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Isoflavonas , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/etiologia , Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miocárdio/metabolismo , Receptores de Adiponectina/efeitos dos fármacos , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , EstreptozocinaRESUMO
BACKGROUND: The gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) has recently been recognized to be one of the risk factors for cardiovascular disease (CVD). However, there is a scarcity of data on the relationship between circulating TMAO levels and hypertension in patients with CVD. Meta analysis and a dose-response relationship were used in this study to assess the relationship between circulating trimethylamine N-oxide levels and the risk of hypertension in patients with CVD. METHODS: CNKI, Wanfang Database, Pubmed, Embase, Cochrane Library, and Web of Science were searched up to June 01, 2023. Meta-analysis and dose-response analysis of relative risk data from prospective cohort studies reporting on the relationship between circulating TMAO levels and hypertension risk in patients with CVD were conducted. RESULTS: Fifteen studies with a total of 15,498 patients were included in the present meta-analysis. Compared with a lower circulating TMAO level, a higher TMAO level was associated with a higher risk of hypertension in patients with CVD (RRâ =â 1.14,95%CI (1.08, 1.20)). And the higher the TMAO level, the greater the risk of hypertension. The dose-response analysis revealed a linear dose-response relationship between circulating TMAO levels and the risk of hypertension in patients with CVD. The risk of hypertension increased by 1.014% when the circulating TMAO level increased by 1 µ mol/L. CONCLUSION: In patients with CVD, the level of circulating TMAO is significantly related to the risk of hypertension. The risk of hypertension increased by 1.014% for every 1 µ mol/L increase in circulating TMAO levels.
Assuntos
Doenças Cardiovasculares , Hipertensão , Metilaminas , Humanos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Hipertensão/sangue , Hipertensão/epidemiologia , Metilaminas/sangue , Estudos ProspectivosRESUMO
Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
Assuntos
Metabolismo Energético , Peptídeos Semelhantes ao Glucagon , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Masculino , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Metabolismo Energético/efeitos dos fármacos , Camundongos , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Camundongos Endogâmicos C57BL , Remodelação Ventricular/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismoRESUMO
Background: Continuous light exposure increases sympathetic excitation in rats, leading to hypertension, left ventricular hypertrophy, and fibrosis. This study was aimed to investigate whether continuous light exposure causes destabilization of vital signs and gut microbiota (GM) in Sprague Dawley (SD) rats and whether clonidine hydrochloride (CH), a central sympathetic depressant drug, could prevent these changes. Methods: Eight-week-old male SD rats were divided into three groups with different interventions for 14 weeks: control group (CG), 2-mL pure water gavaged daily while on a normal 12-h light/dark cycle; continuous illumination group (CI), 2-mL pure water gavaged daily while receiving continuous exposure to light (300 lx); and drug administration group (DA), CH (10 µg/kg) gavaged daily while receiving continuous exposure to light (300 lx). Results: The results showed that blood pressure, heart rate, and body weight were significantly higher in the CI group than in the CG and DA groups (P < 0.05). Moreover, the Shannon index was higher in the DA group than in the CI group (P = 0.012). The beta diversity index in the CG group was significantly higher in the CI group (P = 0.039). The pairwise comparison results of the linear discriminant analysis effect size showed that Oscillospirales were enriched in the DA group, whereas the Prevotellaceae lineage (family level) > Prevotella (genus level) > Prevotellaceae_bacterium (species level) were enriched in the CI group. The Muribaculaceae family was more abundant in the CG group than in the CI group. Conclusion: Sympathetic nerve inhibition restored the abnormal vital signs and GM changes under continuous light exposure.
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Background: Dilated cardiomyopathy (DCM) is characterized by enlarged ventricular dimensions and systolic dysfunction and poor prognosis. Myocardial lipid metabolism appears abnormal in DCM. However, the mechanism of lipid metabolism disorders in DCM remains unclear. Methods: A gene set variation analysis (GSVA) were performed to estimate pathway activity related to DCM progression. Three datasets and clinical data downloaded from the Gene Expression Omnibus (GEO), including dilated cardiomyopathy and donor hearts, were integrated to obtain gene expression profiles and identify differentially expressed genes related to lipid metabolism. GO enrichment analyses of differentially expressed lipid metabolism-related genes (DELs) were performed. The clinical information used in this study were obtained from GSE21610 dataset. Data from the EGAS00001003263 were used for external validation and our hospital samples were also tested the expression levels of these genes through RT-PCR. Subsequently, logistic regression model with the LASSO method for DCM prediction was established basing on the 7 DELs. Results: GSVA analysis showed that the fatty acid metabolism was closely related to DCM progression. The integrated dataset identified 19 DELs, including 8 up-regulated and 11 down-regulated genes. A total of 7 DELs were identified by further external validation of the data from the EGAS00001003263 and verified by RT-PCR. By using the LASSO model, 6 genes, including CYP2J2, FGF1, ETNPPL, PLIN2, LPCAT3, and DGKG, were identified to construct a logistic regression model. The area under curve (AUC) values over 0.8 suggested the good performance of the model. Conclusion: Integrated bioinformatic analysis of gene expression in DCM and the effective logistic regression model construct in our study may contribute to the early diagnosis and prevention of DCM in people with high risk of the disease.
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BACKGROUND AND PURPOSE: Limonin, a naturally occurring tetracyclic triterpenoid, has extensive pharmacological effects. Its role in cardiac hypertrophy remains to be elucidated. We investigated its effects on cardiac hypertrophy along with the potential mechanisms involved. EXPERIMENTAL APPROACH: The effects of limonin on cardiac hypertrophy in C57/BL6 mice caused by aortic banding, plus neonatal rat cardiac myocytes (NRCMs) stimulated with phenylephrine to induce cardiomyocyte hypertrophy in vitro were investigated. KEY RESULTS: Limonin markedly improved the cardiac function and heart weight in aortic banded mice. Limonin-treated mice and NRCMs also produced fewer cardiac hypertrophy markers than those treated with the vehicle in the hypertrophic groups. Sustained aortic banding- or phenylephrine-stimulation impaired cardiac sirtuin 6 (SIRT6) protein levels, which were partially reversed by limonin associated with enhanced activity of PPARα. Sirt6 siRNA inhibited the anti-hypertrophic effects of limonin in vitro. Interestingly, limonin did not influence Sirt6 mRNA levels, but regulated ubiquitin levels. Thus, the protein biosynthesis inhibitor, cycloheximide and proteasome inhibitor, MG-132, were used to determine SIRT6 protein expression levels. Under phenylephrine stimulation, limonin increased SIRT6 protein levels in the presence of cycloheximide, but it did not influence SIRT6 expression in the presence of MG-132, suggesting that limonin promotes SIRT6 levels by inhibiting its ubiquitination degradation. Furthermore, limonin inhibited the degradation of SIRT6 by activating ubiquitin-specific peptidase 10 (USP10), while Usp10 siRNA prevented the beneficial effects of limonin. CONCLUSION AND IMPLICATIONS: Limonin mediates the ubiquitination and degradation of SIRT6 by activating USP10, providing an attractive therapeutic target for cardiac hypertrophy.
Assuntos
Limoninas , Sirtuínas , Animais , Cardiomegalia/metabolismo , Cicloeximida/metabolismo , Cicloeximida/farmacologia , Limoninas/metabolismo , Limoninas/farmacologia , Camundongos , Miócitos Cardíacos , Fenilefrina/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Sirtuínas/metabolismo , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/farmacologiaRESUMO
An important pathophysiological consequence of pressure overload-induced cardiac hypertrophy is adverse cardiac remodeling, including structural changes in cardiomyocytes and extracellular matrix. Diosmetin (DIO), a monomethoxyflavone isolated from citrus fruits, had antioxidative stress effects in multiple organs. The purpose of this study was to examine the biological effect of diosmetin on pathological cardiac hypertrophy. In mice, diosmetin treatment reduced cardiac hypertrophy and dysfunction in an aortic banding- (AB-) induced pressure overload model and reducing myocardial oxidative stress by increasing antioxidant gene expression. In vitro, diosmetin (10 or 50 µm, 12 h or 24 h) protected PE-induced cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Mechanistically, diosmetin inhibited autophagy by activating the PI3K/Akt pathway. In particular, diosmetin induced the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of Nrf2, and increased the expression of antioxidant stress genes in the process of cardiac hypertrophy. Furthermore, knockdown of p62 in rat primary cardiomyocytes abrogate the protective effect of diosmetin on cardiomyocyte hypertrophy. Similarly, the Nrf2 inhibitor ML385 obviously abolished the above effects by diosmetin treatment. In conclusion, our results suggest that diosmetin protects cardiac hypertrophy under pressure overload through the p62/Keap1/Nrf2 signaling pathway, suggesting the potential of diosmetin as a novel therapy for pathological cardiac hypertrophy.
Assuntos
Antioxidantes/administração & dosagem , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Flavonoides/administração & dosagem , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos , Ratos Sprague-Dawley , Proteína Sequestossoma-1/genética , Transdução de Sinais/genética , Transfecção/métodos , Resultado do TratamentoRESUMO
Indigenous animals show unique gut microbiota (GM) in the Tibetan plateau. However, it is unknown whether the hypertensive indigenous people in plateau also have the distinct gut bacteria, different from those living in plains. We sequenced the V3-V4 region of the gut bacteria 16S ribosomal RNA (rRNA) gene of feces samples among hypertensive patients (HPs) and healthy individuals (HIs) from 3 distinct altitudes: Tibetans from high altitude (3600-4500 m, n = 38 and 34), Hans from middle altitude (2260 m, n = 49 and 35), and Hans from low altitude (13 m, n = 34 and 35) and then analyzed the GM composition among hypertensive and healthy subgroups using the bioinformatics analysis, respectively. The GM of high-altitude Tibetan and middle-altitude Han HPs presented greater α- and ß-diversities, lower ratio of Firmicutes/Bacteroidetes (F/B), and higher abundance of beneficial Verrucomicrobia and Akkermansia than the low-altitudes HPs did. The GM of high-altitude Tibetan and middle-altitude HIs showed greater α-diversity and lower ratio of F/B than the low-altitudes HIs did. But, ß-diversity and abundance of Verrucomicrobia and Akkermansia among different subgroups of HIs did not show any differences. Conclusively, the high-altitude Tibetan and middle-altitude Han HPs have a distinct feature of GM, which may be important in their adaptation to hypertension in the plateau environments.
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MicroRNA (miRNA, miR)-155 is the most promising pro-inflammatory miRNA molecule. Lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL) are the most well-known foreign antigens, initiating immune responses against infection and the development of atherosclerosis (AS), respectively. To explore whether miR-155 is involved in regulating LPS- and oxLDL-initiated inflammations, we investigated the level of miR-155 in both LPS- and oxLDL-treated RAW264.7 cells, assessed whether miR-155 induce morphologic changes of the cells and how did it regulate the production of surface markers and cytokines. The results showed that the level of miR-155 was significantly increased by LPS and was modestly increased by oxLDL. Moreover, RAW264.7 cells displayed morphological transformations from macrophage-like cells into DC-like cells when miR-155 was over-expressed. Furthermore, the gain- and loss-of-function studies demonstrated that miR-155 induced the expression of the surface markers (including MHC-II, MHC-I, CD86, and CD83) and pro-inflammatory cytokines (including interleukin (IL)-12, IL-6, and IL-1b) in both LPS- and oxLDL-treated RAW264.7 cells. Additionally, miR-155 induced the expression of CD36 in oxLDL-treated RAW264.7 cells. In conclusion, up-regulated miR-155 is able to induce morphological and phenotypic changes, and the expression of pro-inflammatory cytokines in both LPS- and oxLDL-treated RAW264.7 cells. Therefore, our study suggests that miR-155 is one important regulator involved in enhancing both LPS- and oxLDL-initiated inflammations, which is critical for the progression of immune responses as well as for the development of AS.
Assuntos
Transdiferenciação Celular , Células Dendríticas/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Animais , Antígenos CD36/metabolismo , Forma Celular , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , MicroRNAs/genética , Fenótipo , Células RAW 264.7 , Fatores de Tempo , Regulação para CimaRESUMO
MicroRNA (miR)-155 is a critical player in both innate and adaptive immune responses. It can influence CD4(+) T cell lineage choice. To clarify the role of miR-155 in CD4(+) CD25(+) regulatory T (Treg)/T helper (Th)17 cell differentiation and function, as well as the mechanism involved, we performed gain-and loss-of-function analysis by transfection pre-miR-155 and anti-miR-155 into purified CD4(+) T cells. The results showed that miR-155 positively regulated both Treg and Th17 cell differentiation. It also induced the release of interleukin (IL)-17A by Th17 cells, but not the release of IL-10 and transforming growth factor (TGF)-ß1 by Treg cells. Furthermore, we found that miR-155 reacted through regulating Janus kinase/signal transducer and activator of transcription (JAK/STAT) rather than TGF-ß/mothers against decapentaplegic homolog (SMAD) signaling pathway in the process of Treg and Th17 cells differentiation. This may because suppressors of cytokine signaling (SOCS)1, the important negative regulator of JAK/STAT signaling pathway, was the direct target of miR-155 in this process, but SMAD2 and SMAD5 were not. Therefore, we demonstrated that miR-155 enhanced Treg and Th17 cells differentiation and IL-17A production by targeting SOCS1.