Endothelial cannabinoid CB1 receptor deficiency reduces arterial inflammation and lipid uptake in response to atheroprone shear stress
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ABSTRACT:
PROVIDER: PRJNA1083581 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR28217687_1.fastq.gz | Fastqsanger.gz | |||
| SRR28217687_2.fastq.gz | Fastqsanger.gz |
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Project description:Peripherally restricted cannabinoid CB1 receptor antagonists without central side effects hold promise for treating metabolic disorders including diabetes and obesity. In atherosclerosis, the specific effects of peripheral CB1 signaling in vascular endothelial cells (ECs) remain incompletely understood.We performed en face in situ hybridization of Cnr1 in murine aortas, revealing a significantly increased expression of the CB1 encoding gene in ECs within atheroprone compared to atheroresistant regions. In vitro, CNR1 was upregulated by oscillatory shear stress in human aortic endothelial cells (HAoECs). Endothelial CB1 deficiency (Cnr1EC-KO) in female mice on atherogenic background resulted in pronounced endothelial phenotypic changes, with reduced vascular inflammation and permeability. This translated into attenuated plaque development with reduced lipid content as well as reduced white and brown adipose tissue mass and liver steatosis. Ex vivo imaging of carotid arteries via two-photon microscopy revealed less DIL-LDL uptake in Cnr1EC-KO. This was accompanied by a significant reduction of aortic endothelial caveolin-1 (CAV1) expression, a key structural protein involved in lipid transcytosis in female Cnr1EC-KO mice. In vitro, pharmacological blocking with CB1 antagonist AM281 reproduced the inhibition of CAV1 expression and LDL uptake in response to atheroprone shear stress in human aortic endothelial cells (HAoECs), which was dependent on cAMP-mediated PKA activation. Conversely, the CB1 agonist ACEA increased DIL-LDL uptake and CAV1 expression in HAoECs. Finally, treatment of atherosclerotic mice with the peripheral CB1 antagonist JD-5037 reduced plaque progression, CAV1 and endothelial adhesion molecule expression in female mice. These results confirm an essential role of endothelial CB1 to the pathogenesis of atherosclerosis.
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Project description:Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cellspecific effects in this disease are not well understood. Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sexspecific differences in proliferation were dependent on estrogen receptor (ER)α estradiol signaling. Kinase activity profiling revealed a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further unveiled chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, hinting to a possible implication of CB1-dependent regulation in human pathophysiology. In conclusion, impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming. The importance of macrophage CB1 signaling seems to be more pronounced in male mice.
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Project description:To profile shear stress-regulated endothelial transcriptomes, we performed RNA-seq with HUVECs subjected to different shear flow conditions, including atheroprotective pulsatile shear (PS, 12±4 dyn/cm2) and atheroprone oscillatory shear (OS, 0.5±4 dyn/cm2), or kept as static control (ST) for four time periods (1, 4, 12 and 24 hours)
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Project description:The cannabinoid 1 receptor (CB1) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1 is expressed on pancreatic beta (β)-cells where its functions have not been fully described. We generated a β-cell-specific CB1-knockout (β-CB1-/-) mouse to study the long-term consequences of CB1 ablation on β-cell function in adult mice. β-CB1-/- mice had increased basal- and stimulated-insulin secretion and intra-islet cAMP levels, resulting in primary hyperinsulinemia, as well as increased β-cell viability, proliferation, and islet area. Hyperinsulinemia led to insulin resistance, which was aggravated by a high fat/high glucose diet and weight gain, although β-cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from β-CB1-/- mice were protected from diet-induced inflammation. Mechanistically we show that this is a consequence of curtailment of oxidative stress and reduced activation of Nlrp3 inflammasome in β-cells. Our data demonstrate CB1 to be a negative regulator of β-cells and a mediator of islet inflammation under conditions of metabolic stress.
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Project description:The goal of this study was to find longitudinal transcriptional response of human aortic endothelial cells (HAECs) to pulsatile shear (PS) and oscillatory shear (OS) and compare them with the responses in human umbilical vein endothelial cells (HUVECs) [GSE103672]. PS is associated with an atheroprotective endothelial phenotype, while OS is associated with an atheroprone endothelial phenotype. Using RNASeq method (single-ended 75-bp sequencing on Illumina Hi-seq 4000 instrument), we measured the transcriptional response at 3 time-points (1, 4, and 24 hrs) under PS and OS conditions. Measurements were also taken under static condition (ST, no flow) at t = 0 hr. Three replicates were used for each condition/time-point. Our results indicate that the responses of HAECs and HUVECs are qualitatively similar for endothelial-function relevant genes and several important pathways with a few exceptions, thus demonstrating that HUVECs can be used as a model to investigate the effects of shear on arterial ECs, with some reservations. Our findings show that HAECs exhibit an earlier response or faster kinetics as compared to HUVECs. The comparative analysis in this study offers new insights into the mechanisms of common and disparate stress responses across these two endothelial cell types.
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Project description:Cerebral ischemia, commonly resulting from an ischemic stroke, can lead to significant cognitive impairments due to neuronal damage and neuroinflammation. The cannabinoid CB1 receptor, part of the endocannabinoid system, plays a crucial role in modulating synaptic plasticity, neurogenesis, and neuroprotection. Research suggests that targeting the CB1 receptor could offer a promising therapeutic strategy to mitigate cognitive deficits following cerebral ischemia. Modulating CB1 receptor activity, either through agonists or antagonists, has been shown to influence key pathways involved in neuroprotection and inflammation, potentially enhancing recovery of cognitive functions. Understanding the mechanisms by which CB1 receptor modulation affects brain recovery post-ischemia could pave the way for novel treatments aimed at reducing the long-term cognitive impact of ischemic strokes.
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Project description:Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. Recently, the peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 KO mice. In this report, we systematically investigated gene expression changes in peripheral tissues of DIO mice treated with the CB1 inverse agonist AM251. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including SREBP-1 and -2, and their downstream targets in both liver and adipose tissue. In addition, genes involved in fatty acid Beta-oxidation were up-regulated with AM251 treatment, probably through the activation of PPARalpha. In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the TNFalpha signal transduction pathway and possibly to the activation of PPARgamma, both of which would result in improved insulin sensitivity.
2010-06-21 | GSE21069 | GEO
Project description:Long-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB1)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that requires protein synthesis and involves a long-lasting reduction in GABA release. We found that CB1-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB1 activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as Arp2/3, and presynaptic release. Moreover, while CB1-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB1-iLTD. Thus, CB1-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.
2020-09-23 | PXD020008 | Pride