(Pro)renin receptor inhibition reduces plasma cholesterol and triglycerides but does not attenuate atherosclerosis in atherosclerotic mice
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ABSTRACT:
PROVIDER: PRJNA705690 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13816150_1.fastq.gz | Fastqsanger.gz | |||
| SRR13816150_2.fastq.gz | Fastqsanger.gz | |||
| SRR13816151_1.fastq.gz | Fastqsanger.gz | |||
| SRR13816151_2.fastq.gz | Fastqsanger.gz | |||
| SRR13816152_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: to clarify the transcriptomic changes in aortic arch of inhibiting the (pro)renin receptor using (P)RR G-ASOs
2024-03-01 | GSE167972 | GEO
Project description:Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR-/- mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE-/- mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE-/- mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.
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Project description:Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are leading causes of morbidity and mortality in the Western countries. NAFLD is an important independent risk factor for the development of atherosclerosis. The renin-angiotensin system (RAS) with its two main opposing effectors: angiotensin II (Ang II) and Ang-(1-7) is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator – diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE at a dose of 30 mg/kg/day given orally for 16 weeks was able to stabilize atherosclerotic lesions and attenuate hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated HDL in the plasma, decreased triglycerides levels and increased biosynthesis and concentration of taurine in liver of apoE-/- mice. However, the exact molecular mechanisms of both the anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.
2021-09-09 | PXD022829 | Pride
Project description:Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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Project description:Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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Project description:Study of the effect of low-density lipoprotein (LDL)-lowering therapies on the heterogeneous population of proliferating smooth muscle cells (SMCs) derived from atherosclerotic plaques in an atherosclerotic mouse model by inducing hypercholesterolemia followed by high or low fat diet.
2023-12-08 | E-MTAB-12019 | biostudies-arrayexpress
Project description:Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite substantial reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia may be an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides (TGs) and the cholesterol content within triglyceride-rich lipoproteins (TGRLs) and/or remnant cholesterol (RC) in the development of ASCVD. TGRLs are composed of hepatically derived very low-density lipoprotein and intestinally derived chylomicrons. RC is the cholesterol content of all TGRLs and plasma TGs serve as a surrogate measure of TGRLs and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive efficacy in lowering TG levels. Several ongoing, randomized controlled trials are underway to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology, and genetics of TGs and ASCVD; we discuss current and novel TG-lowering therapies under development.
| S-EPMC6416708 | biostudies-literature
Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
2023-12-07 | GSE246083 | GEO
Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
2023-10-31 | GSE246138 | GEO
Project description:Background: Renin-expressing cells are myoendocrine cells crucial for survival which detect changes in blood pressure and release renin to maintain homeostasis. Renin is regulated through several pathways including cAMP, p300/CBP, and BET proteins including Brd4. Binding to the cAMP-responsive element in the renin enhancer region amplifies renin transcription and relies on each of these factors for an appropriate response. The specific regulatory changes that occur following inhibition of these pathways remains understudied. Therefore, we aimed to evaluate chromatin changes and gene signatures that occur following inhibition of renin regulatory factors. Methods: We treated As4.1 cells (a tumoral cell line that constitutively expresses renin) with three inhibitors (H89: PKA inhibition; JQ1: Brd4 inhibition; A-485: p300/CBP inhibition) that target required factors for renin transcriptional regulation. We then performed ATAC-seq, scRNA-seq, and ChIP-seq for H3K27ac and P300 binding on biological replicates of treated and control As4.1 cells. Results: Ren1 expression is significantly, but transiently, reduced following each inhibitory treatment. Further, PKA inhibition leads to corresponding losses in H3K27ac and p300 binding at the locus. A restricted set of nine genes with overlapping dynamically accessible regions, differential gene expression, and H3K27ac and p300 binding were identified with roles across three primary renin regulatory paradigms. Conclusions: The data shows that renin expression is regulated through a switch from an active to poised state of epigenetic control, a shift toward a less differentiated cellular identity via the loss of enhancer elements, and the disruption of cAMP, baroreceptor, and Notch mediated renin regulatory pathways.
2024-08-26 | GSE254943 | GEO