Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE260492 | GEO | 2024/03/05
REPOSITORIES: GEO
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Project description:Pregnancy-associated hypertensive (PAH) mice were maintained by mating females carrying the human angiotensinogen (hAGT) gene with males expressing the human renin (hRN) gene, as previously described (Takimoto E., et al., Science, 1996). Angiotensin II (AngII) has critical roles in regulation of blood pressure. In late pregnancy of PAH mice, increased AngII causes acute and severe hypertension with proteinuria. Furthermore, PAH mice show cardiac hypertrophy, fibrosis and apoptosis. It is known that AngII downregulates mRNA of alpha 1a-adrenergic receptor (Adra1a) in neonatal rat cardiac myocytes (Li H.T., et al., Circ. Res., 1997). Interestingly, we found that Adra1a knock out PAH (PAH/aKO) mice display more severe phenotype of cardiac hypertrophy in comparison to PAH mice. In this study, to understand the molecular basis of cardiac hypertrophy via regulation of Adra1a expression with AngII in PAH mice, we performed a comprehensive analysis of gene expression changes in cardiac remodeling of PAH and PAH/aKO mice using the next-generation RNA sequencing (RNA-seq).
2023-01-27 | GSE140948 | GEO
Project description:Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway.
2022-04-09 | GSE200279 | GEO
Project description:Abstract Background: Long-term hypertension can lead to hypertensive heart disease, which ultimately progresses to heart failure. As an angiotensin receptor blocker (ARB) antihypertensive drug, allisartan can control blood pressure and improve cardiac remodeling and cardiac dysfunction caused by hypertension. The objective of this study is to investigate the protective effects of Allisartan on the heart of spontaneously hypertensive rats (SHRs) and the underlying mechanisms. Methods: We used spontaneously hypertensive rats (SHRs) as an animal model of hypertensive heart disease and treated them with allisartan orally at a dose of 25 mg/(Kg·day). We continuously monitored the rats' blood pressure levels, measured their body and heart weights, and evaluated their cardiac structure and function using echocardiography. WGA staining and Masson trichrome staining were employed to assess the morphology of the myocardial tissue. We performed transcriptome and proteome analysis using the Solexa/Illumina sequencing platform and tandem mass tag (TMT) technology, respectively. We used immunofluorescence co-localization to analyze Nrf2 nuclear translocation, and TUNEL to detect the level of cell apoptosis. The protein and mRNA levels were determined by Western blotting and qRT-PCR, respectively. Results: Allisartan lowered blood pressure, attenuated cardiac remodeling, and improved cardiac function. Allisartan alleviated cardiomyocyte hypertrophy and cardiac fibrosis. Allisartan significantly affected the pentose phosphate pathway, fatty acid elongation, valine, leucine and isoleucine degradation, glutathione metabolism, and amino sugar and nucleotide sugar metabolism pathways in the hearts of SHRs, and upregulated the expression level of GSTM2. Allisartan activated the PI3K-AKT-Nrf2 signaling pathway and inhibited cardiomyocyte apoptosis. Conclusions: Our study determined that allisartan effectively controls blood pressure in SHRs and improves cardiac remodeling and cardiac dysfunction. Allisartan upregulates the expression level of GSTM2 in the hearts of SHRs and significantly affects glutathione metabolism shown by transcriptomics and proteomics analysis. The cardioprotective effect of allisartan may be mediated through activation of the PI3K-AKT-Nrf2 signaling pathway, upregulation of GSTM2 expression, and reduction of SHRs cardiomyocyte apoptosis.
2024-02-27 | GSE254800 | GEO
Project description:Obesity-induced secretory disorder of adipose tissue-derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in Angiotensin II (AngII)-infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue, as well as more severe cardiac remodeling compared to control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow specific uPA knockdown decreased active PDGF-DD level in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte, that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.
2021-05-27 | GSE175572 | GEO
Project description:Analysis of cardiac specific AT1 transgenic mice undergoing cardiac failure, cardiac hypertrophy and wild type aged matched controls. For detailed description of the AT1 Tg mice please refer to:; Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):931-6. PMID: 10639182 [PubMed - indexed for MEDLINE]
2008-06-12 | E-GEOD-2355 | biostudies-arrayexpress
Project description:Cardiovascular disease (CVD) in chronic kidney disease (CKD) is characterized by vascular calcification and cardiac remodeling. CKD induced cardiac hypertrophy precedes cardiac fibrosis and is associated with left ventricular dysfunction. Elevated phosphate concentration due to renal failure is known to be involved in cardiac remodeling.
2016-10-25 | GSE89130 | GEO
Project description:The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders. The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet–feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)–induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat). Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery. These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.
2023-07-13 | GSE237063 | GEO
Project description:Background: Heart failure (HF), characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of N-acetyltransferase 10 (NAT10)-mediated N4?acetylcytidine (ac4C) acetylation during cardiac remodeling. Methods: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing (acRIP-seq), thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified post-transcriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II and transverse aortic constriction (TAC). Results: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardio-fibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to TAC by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. Conclusions: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.
2023-10-31 | GSE233736 | GEO
Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .
2009-06-06 | E-GEOD-16199 | biostudies-arrayexpress
Project description:Analysis of cardiac specific AT1 transgenic mice undergoing cardiac failure, cardiac hypertrophy and wild type aged matched controls. For detailed description of the AT1 Tg mice please refer to: Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):931-6. PMID: 10639182 [PubMed - indexed for MEDLINE] Keywords: ordered
2005-06-15 | GSE2355 | GEO