The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid-Serum raw data
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ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Blood
PROVIDER: ST000452 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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| ST000451 | MetabolomicsWorkbench
Project description:IntroductionAlpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied.ObjectivesGiven the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo.MethodsMice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach.ResultsWe identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs).ConclusionGiven the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.
| S-EPMC5437747 | biostudies-literature
Project description:Aims: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Chronic β-AR activation causes maladaptive alterations in cardiomyocyte metabolism that contribute to the pathobiology of heart failure. In contrast, mounting evidence suggests that a1-ARs, particularly the a1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared endogenous catecholamine ligands. The mechanisms through which a1A-ARs exert their cardioprotective effects remain unclear. Here we tested the hypothesis that a1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and failing heart.
Methods: We characterized the effects of global α1A-AR genetic deletion on mitochondrial function and metabolism in the uninjured mouse heart using high resolution respirometry, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM), proteomics, and lipidomics. We then compared the effects of α1A- and β-AR agonist treatment on ETC enzyme activity and oxidative stress in vivo and in vitro. We subjected wild type and cardiomyocyte-specific α1A-KO mice to permanent left coronary artery (LCA) ligation and used RNAseq to compare the transcriptomic response. Results: We found that isolated cardiac mitochondria from mice with global α1A-AR genetic deletion (α1A-KO) had deficits in fatty acid-dependent respiration and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 (100 ng/kg/d, 3d) enhanced fatty acid oxidation (FAO) in isolated cardiac mitochondria while increasing expression and activity of the mitochondrial trifunctional protein, a critical FAO mediator. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. RNAseq revealed broad basal deficits in pathways related to mitochondria and OXPHOS in cardiomyocyte-specific α1A-KO mice; these differences were exaggerated by LCA ligation. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction.
Conclusions: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.
2024-08-15 | PXD044591 | JPOST Repository
Project description:Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRα remains unknown. We investigated whether LXRα binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXRα activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXRα. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXRα ligand binding pocket similar to the known synthetic agonist of LXRα (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXRα, whereas long-chain FA caused no effect. Our results suggest that LXRα functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length.
| S-EPMC5282955 | biostudies-literature
Project description:BackgroundHeart failure is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of heart failure are poorly understood. The peroxisome proliferator activated receptor-α (PPARα)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent information regulator 1 (Sirt1) is a histone deacetylase, which interacts with PPARα.Methods and resultsTo investigate the role of PPARα in the impaired FA utilization observed during heart failure, genetically altered mice were subjected to pressure overload. The DNA binding of PPARα, RXRα, and Sirt1 to DR1 was evaluated with oligonucleotide pull-down and chromatin immunoprecipitation assays. Although the binding of PPARα to DR1 was enhanced in response to pressure overload, that of RXRα was attenuated. Sirt1 competes with RXRα to dimerize with PPARα, thereby suppressing FA utilization in the failing heart. DR1 sequence analysis indicated that the typical DR1 sequence favors PPARα/RXRα heterodimerization, whereas the switch from RXRα to Sirt1 takes place on degenerate DR1s. Sirt1 bound to PPARα through a region homologous to the PPARα binding domain in RXRα. A short peptide corresponding to the RXRα domain not only inhibited the interaction between PPARα and Sirt1 but also improved FA metabolism and ameliorated cardiac dysfunction.ConclusionsA change in the heterodimeric partner of PPARα from RXRα to Sirt1 is responsible for the impaired FA metabolism and cardiac dysfunction in the failing heart.
| S-EPMC4651813 | biostudies-literature
Project description:Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ERα) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ERα-driven transcription. FASN and ERα were both necessary for the synergistic activation of ERα transcriptional activity that occurred following co-exposure to C75 and E2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E2 required for optimal activation of ERα-mediated transcriptional activity; second, FASN blockade synergistically increased E2-stimulated ERα-mediated transcriptional activity in ERα-negative breast cancer cells stably transfected with ERα, but not in ERα-negative parental cells. Non-genomic, E2-regulated cross-talk between the ERα and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ERα transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ERα protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. The ability of FASN to regulate E2/ERα signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.
| S-EPMC5337623 | biostudies-literature
Project description:BackgroundProinflammatory cytokine tumor necrosis factor-α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known.Methods and resultsTwo different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling βAR desensitization independent of sympathetic overdrive. TNFα-mediated βAR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in β2AR-overexpressing human embryonic kidney 293 cells showed significant βAR desensitization, GRK2 upregulation, and recruitment to the βAR complex following TNFα. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated βAR phosphorylation and GRK2 recruitment on TNFα. Furthermore, TNFα-mediated βAR phosphorylation was not blocked with βAR antagonist propranolol. Additionally, TNFα administration in transgenic mice with cardiac overexpression of Gβγ-sequestering peptide βARK-ct could not prevent βAR desensitization or cardiac dysfunction showing that GRK2 recruitment to the βAR is Gβγ independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNFα-mediated βAR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNFα-mediated loss in contractility, showing that TNFα-induced βAR desensitization is GRK2 dependent.ConclusionsTNFα-induced βAR desensitization is mediated by GRK2 and is independent of Gβγ, uncovering a hitherto unknown cross-talk between TNFα and βAR function, providing the underpinnings of inflammation-mediated cardiac dysfunction.
| S-EPMC3874808 | biostudies-literature
Project description:Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.
| S-EPMC5696080 | biostudies-literature
Project description:β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by β-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the β-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of β-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates β-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.
| S-EPMC9061800 | biostudies-literature
Project description:The α2-adrenergic receptor (α2-AR) is widely distributed in the brain with distinct roles for α2-AR subtypes (A, B and C). In this article, data are provided on Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 expression in the brain of the α2A-AR knockout (α2A-AR KO) mouse. These data are supplemental to an original research article examining Arc and Zif268 expression in rats injected with the α2-AR antagonist, RX821002 (http://dx.doi.org/10.1016/j.neulet.2015.12.002. [1]).
| S-EPMC4761656 | biostudies-literature