Estrogen receptor α deficiency in cardiac myocytes reprograms heart-derived extracellular vesicle proteome and induces obesity in female mice (Part 1)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Liver, Muscle, Epididymal Fat, Ventricles, Blood
DISEASE(S): Obesity
PROVIDER: ST002229 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description: Not available
| ST002228 | MetabolomicsWorkbench
Project description:Dysregulation of ER has been linked with increased metabolic and cardiovascular disease risk. Uncovering the impact of ERα deficiency in specific tissues has implications for understanding the role ERα in normal physiology and disease, the increased disease risk in postmenopausal women, and the design of tissue-specific ERα-based therapies for a range of pathologies including cardiac disease and cancer. Cardiac myocyte-specific ER knockout mice (ERHKO) were generated to assess the role of ERα in the heart. Female ERHKO mice displayed a mild cardiac phenotype, but unexpectedly, the most striking phenotype was obesity in female ERHKO but not male ERHKO mice. We identified contractile dysfunction, metabolic and lipid dysregulation in hearts of female ERHKO mice. We also show that extracellular vesicles (EVs) collected from the perfusate from Langendorff-isolated hearts from female ERHKO mice contained distinct proteins with functions related to muscle, metabolic and fatty acid dysregulation.
2023-01-15 | PXD027811 | Pride
Project description:Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. GPER KO mice also displayed increased heart weight, cardiac collagen deposition, and Doppler-derived filling pressure, and decreased percent fractional shortening and early mitral annular velocity compared with WT controls. Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss.
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Project description:Background and aimsAlpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with liver disease, ranging from fibrosis to hepatocellular carcinoma. The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy. Biomarkers offer an advantage for disease evaluation. The presence of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) presents a noninvasive approach to assess the molecular signatures of the disease. In this study, we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals.MethodsUsing small RNA sequencing and qPCR, we examined plasma EV miRNAs in healthy controls (n = 20) and AATD patients (n = 17). We compared the EV miRNAs of AATD individuals with and without liver disease, developing an approach for detecting liver disease. A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients (n = 45).ResultsWe identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls. We categorized AATD individuals into those with and without liver disease, identifying 39 differentially expressed miRNAs. Six miRNAs were selected to test their ability to discriminate liver disease in AATD. These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals. Our logistic model established composite scores with three- and four-miRNA combinations, achieving areas under the curve of 0.737 and 0.751, respectively, for predicting AATD liver disease.ConclusionsWe introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease. Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.
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Project description:Malignant melanoma is one of the most aggressive types of cancer, and its incidence is increasing rapidly each year. Despite the extensive research into improved diagnostic and treatment methods, early detection and disease constraint still present significant challenges. As successful isolation protocols have been developed, extracellular vesicles (EVs) have become the subject of extensive investigation in terms of their role in cancer progression and as a possible source of disease biomarkers. Besides functional studies, quantitative and qualitative proteomics have recently emerged as promising tools for the advancement of melanoma biomarkers. Nevertheless, the amount of data concerning the proteome of melanoma-derived EVs is still very limited. In this review we cover the current knowledge on protein content of melanoma-derived EVs, with a focus on their potential role in the development and progression of melanomas.
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Project description:Estrogen improves insulin sensitivity and increases energy expenditure, contributing to sexual dimorphism regarding type 2 diabetes mellitus (T2DM) susceptibility. Estrogen receptor α (ERα) plays a crucial role in mediating estrogen action on glucose and energy homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we found a ligand-independent effect of ERα on the regulation of glucose homeostasis and identified an ERα-derived peptide as a potential insulin sensitizer. Deficiency of ERα but not ERβ in the liver impaired glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies revealed that ERα promoted hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediated the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we designed a peptide based on ERα 1-280 domain and found that ERα-derived peptide interacted with IRS1, increased IRS1 stability through suppressing its ubiquitination, and enhanced insulin sensitivity. Importantly, administration of ERα-derived peptide into obese mice significantly increased insulin sensitivity, attenuated glucose intolerance, and improved serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERα and indicate that ERα-derived peptide is a potential insulin sensitizer for the treatment of T2DM.
2024-04-05 | GSE262841 | GEO
Project description:Polycystic ovary syndrome (PCOS), a metabolic and reproductive disease, is frequently associated with type 2 diabetes. We have demonstrated activating autoantibodies (AAb) directed toward the second extracellular loop (ECL2) of the gonadotropin-releasing hormone receptor (GnRHR) are present in a significant subgroup of PCOS patients. It is unclear whether GnRHR-AAb can induce peripheral tissue insulin resistance (IR) in animal models. Sixteen rats were divided equally into a GnRHR ECL2 peptide-immunized group (IMM group) and a control group (CON group). Sera GnRHR-AAb titer, luteinizing hormone (LH), and testosterone (T) were higher in IMM rats compared with CON rats. No significant difference in fasting blood glucose was observed between the two groups. However, the plasma glucose level at other time points of the IMM group was higher than that of the CON group during an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT) (p < 0.01). These data support the likelihood of the GnRHR-AAb induction of glucose intolerance and IR. Compared with the CON group, the IMM group showed a significant increase in insulin-stimulated phosphorylation of IRS-1 (p-IRS-1 S636/639) and a decrease in insulin-stimulated phosphorylation of Akt (p-AKT S473). Expression of the glucose transport genes including GLUT-2 in liver and GLUT-4 in white adipose tissue and skeletal muscle was significantly decreased in IMM rats compared with the CON rats. Serum levels of proinflammatory cytokines (TNF-α, IL-1α, and IL-18) were increased, while anti-inflammatory cytokines (IL-4 and IL-10) were decreased in the IMM group. Taken together, elevated GnRHR-AAb enhanced LH, hyperandrogenism, and inflammation. These changes are likely related to the observed peripheral tissue IR through the downregulation of the insulin-stimulated IRS/PI3K/Akt/Glut signaling pathway.
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