Empagliflozin Ameliorates Aldehyde Dehydrogenase 2 Deficiency-induced Endothelial Dysfunction
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184419 | GEO | 2023/03/30
REPOSITORIES: GEO
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Project description:Empagliflozin Ameliorates Aldehyde Dehydrogenase 2 Deficiency-induced Endothelial Dysfunction
| PRJNA764589 | ENA
Project description:Aged hematopoietic stem cells (HSC) display diminished self-renewal and a myeloid differentiation bias. However, the physiological drivers and molecular processes that underpin this fundamental switch are not understood. HSCs produce formaldehyde and are protected from this metabolite by two tiers of protection: the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. Using single cell RNA sequencing, we find that the HSC and progenitor cells in young Aldh2-/- Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition and myeloid-biased progenitors. In addition, the p53 response is vigorously activated in Aldh2-/- Fancd2-/- HSCs, whilst p53 deletion rescued this aged transcriptomic signature and telomere attrition. Transplantation of single Aldh2-/- Fancd2-/- HSCs also reveals a predominantly myeloid output, which is reversed upon p53 deletion. To further define the origins of the myeloid differentiation bias, a GFP genetic reporter which detects Vwf+ myeloid primed HSCs was crossed into Aldh2-/- Fancd2-/- mice, revealing a striking enrichment of these lineage-biased Vwf+ HSCs. These results indicate that metabolism derived formaldehyde causes endogenous DNA damage which stimulates the p53 response in HSCs, which then accelerates their aging, resulting in a myeloid lineage biased output.
2023-05-24 | GSE209742 | GEO
Project description:We conducted RNA sequcing of the fresh and 1-week recoverd human induced pluripotent stem cell-derived caridomyocytes (hiPSC-CMs) undergo cryopreservation
2021-03-03 | GSE146266 | GEO
Project description:Recently, it has been shown that mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of neurodegeneration. Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes – the end products of lipid peroxidation, is considered to exert protective function in mitochondria. The aim of our study was to use the methods of differential proteomics in concert with molecular and morphological techniques to elucidate the changes in the frontal cortex and hippocampus of apolipoprotein E knockout (apoE-/-) mice (an animal model of the early stages of Alzheimer’s disease) upon treatment with Alda-1 – a small molecular weight activator of ALDH2.
2017-02-23 | PXD004022 | Pride
Project description:Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2, a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.
| S-EPMC7555032 | biostudies-literature
Project description:Introduction: Endothelial cells (ECs) form the inner lining of all blood vessels of the body, play important roles in vascular tone regulation, hormone secretion, anticoagulation, regulation of blood cell adhesion and immune cell extravasation. Limitless ECs sources are required to further in-vitro investigations of ECs’ physiology and pathophysiology as well as for tissue engineering approaches. Ideally, the differentiation protocol avoids animal derived components such as fetal serum and yields ECs at efficiencies that make further sorting obsolete for most applications. Method: hiPSC are cultured under serum free conditions, and induced into mesodermal progenitor cells via stimulation of Wnt signaling for 24 hours. Mesodermal progenitor cells are further differentiated into ECs by utilizing a combination of human vascular endothelial growth factor A165 (VEGF), basic fibroblast growth factor (bFGF), 8-Bromoadenosine 3′,5′-cyclic monophosphate sodium salt monohydrate (8Bro), and melatonin (Mel) for 48 hours. Result: This combination generates hiPSC derived ECs (hiPSC-ECs) at a fraction of 90.9 ± 1.5% and is easily transferable from the two dimensional (2D) mono layer into three dimensional (3D) scalable bioreactor suspension cultures. hiPSC-ECs are positive for CD31, VE-Cadherin, von-Willebrand-factor, and CD34. Furthermore, the majority of hiPSC-ECs express the vascular endothelial marker CD184 (CXCR4). Conclusion: The differentiation method presented here generates hiPSC-ECs in only 6 days, without addition of animal sera and at an efficiency eliminating the need for further enrichment strategies, hence providing a scalable source of hiPSC-ECs.
2022-04-08 | GSE200399 | GEO
Project description:Reactive aldehydes arise as by-products of metabolism, and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is profoundly disrupted, with a reduction of hematopoietic stem cells and also common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is the common substrate of ALDH2 and ADH5, and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone marrow derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to ageing-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a new inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.
2020-09-21 | GSE157832 | GEO
Project description:Chronic alcohol intake leads to insulin resistance and alcoholic cardiomyopathy, which appears to be a result of the complex interaction between genes and environment. This study was designed to examine the impact of aldehyde dehydrogenase-2 (ALDH2) transgenic overexpression on alcohol-induced insulin resistance and myocardial injury. ALDH2 transgenic mice were produced using chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were fed a 4% alcohol or control diet for 12 weeks. Cell shortening was evaluated using an edge-detection system. Western blot analysis was used to assess insulin signaling at the levels of receptor, IRS, Akt, GSK-3beta, the transcription factors Foxo3a, c-Jun amino-terminal kinase (JNK) and c-Jun. Chronic alcohol intake led to glucose intolerance, reduced glucose uptake, cardiac hypertrophy and reduced cell shortening, the effects of which were alleviated by ALDH2. ALDH2 significantly attenuated alcohol-induced decrease in the insulin-stimulated tyrosine phosphorylation and increase in serine phosphorylation of IRS. Phosphorylation of Akt, GSK-3beta and Foxo3a was reduced following alcohol intake, the effect of which was abrogated by ALDH2. Levels of JNK, c-Jun and their phosphorylation were elevated following chronic alcohol intake, which were obliterated by ALDH2. Transfection of H9C2 myoblast cells with Foxo3a adenovirus mimicked acetaldehyde-induced JNK activation and glucose uptake defect whereas the dominant negative Foxo3a ablated acetaldehyde-elicited insulin insensitivity. In addition, ALDH2 reversed alcohol-induced myocardial ER stress. These data revealed that ALDH2 overexpression antagonizes chronic alcohol intake-induced cardiac insulin insensitivity and contractile defect, possibly via improvement of insulin signaling at the levels of insulin receptor, IRS, Akt, Foxo3a and JNK.
| S-EPMC2703697 | biostudies-literature
Project description:Human induced pluripotent stem cells (hiPSCs) are used to study organogenesis and model disease as well as being developed for regenerative medicine. Endothelial cells are among the many cell types differentiated from hiPSC, but their maturation and stabilization fall short of that in adult endothelium. We examined whether shear stress alone or in combination with pericyte co-culture would induce flow alignment and maturation of hiPSC-derived endothelial cells (hiPSC-ECs) but found no effects comparable to those in primary microvascular EC. In addition, hiPSC-ECs lacked a luminal glycocalyx, critical for vasculature homeostasis, shear stress sensing and signalling. We noted however, that hiPSC-EC have dysfunctional mitochondrial permeability transition pores, resulting in reduced mitochondrial function and increased reactive oxygen species (ROS). Closure of these pores by cyclosporine-A improved EC mitochondrial function but also restored the glycocalyx such that alignment to flow took place. These indicated that mitochondrial maturation is required for proper hiPSC-EC functionality.
2019-12-14 | E-MTAB-8392 | biostudies-arrayexpress
Project description:Aims/hypothesis Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. Methods We generated an Aldh1b1-knockout mouse line (Aldh1b1tm1lacZ) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. Results Differentiation in the developing pancreas of Aldh1b1tm1lacZ null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. Conclusions/interpretation These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life.
2015-07-31 | GSE58025 | GEO