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USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

ABSTRACT: Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25.

ORGANISM(S): Mus musculus

PROVIDER: GSE221396 | GEO | 2023/03/01

REPOSITORIES: GEO

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USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

Project description:USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

| PRJNA914241 | ENA

Heart mRNA profiles of TAC 8-weeks wild type (WT) and miR-27b-3p knockout mice

Project description:Aim: The heart undergoes pathological remodelling under increased stress and neuronal imbalance. MicroRNAs (miRNAs) are involved in post-transcriptional regulation of genes in cardiac physiology and pathology. However, the mechanisms underlying miRNA-mediated regulation of pathological cardiac remodelling remain to be studied. This study aims to explore the function of endogenous microRNA-27b-3p (miR-27b-3p) in pathological cardiac remodelling. Methods and results: We found that miR-27b-3p expression was elevated in heart of patients with cardiac hypertrophy and in transverse aortic constriction (TAC)-induced cardiac hypertrophy mouse model. MiR-27b-3p-knockout mice showed significantly attenuated cardiac hypertrophy, fibrosis, and inflammation induced by two independent pathological cardiac hypertrophy models, TAC and Angiotensin II (Ang II) perfusion. Transcriptome sequencing analysis revealed that miR-27b-3p deletion significantly downregulated TAC-induced cardiac hypertrophy, fibrosis, and inflammatory genes. We identified fibroblast growth factor 1 (FGF1) as a novel miR-27b-3p target gene in the heart, which was upregulated in miR-27b-3p-null mice. Conclusions: Our study has demonstrated that miR-27b-3p induces pathological cardiac remodelling and suggests that inhibition of endogenous miR-27b-3p or administration of FGF1 might have the potential to suppress cardiac remodelling in a clinical setting.

2022-07-27 | GSE158191 | GEO

Gastrodin alleviates cardiac hypertrophy by inhibition of insulin-like growth factor type 2/insulin-like growth factor type 2 receptor

Project description:Background: Pathological cardiac hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and leads to heart failure. Previous studies demonstrated that gastrodin (GAS) inhibited cardiac hypertrophy and thus improved cardiac function. However, the theraputic targets by which GAS regulates in the regression of cardiac hypertrophy has not been well elucidated yet. Methods: A mouse model of myocardial hypertrophy was estavlished by angiotensin II (Ang II) induction, then treated with GAS (0, 5 or 50 mg/kg/d) combined with the sham-operated controls. Heart samples from each dose group were collected for the next RNA sequencing.Through bioinformatics analysis, the key differentially expressed genes (DEG) involved in the recovery of cardiac function were identidied. They were further confirmed by quantitative real-time PCR (qRT-PCR) and western blotting in neonatal rat cardiomyocytes (NRCMs). Results: We identified 620 up-regulated and 87 down-regulated DEGs induced by Ang II, of which the expression patterns of 58 and 146 genes were reversed by low-dose and high-dose GAS, respectively. These reversed DEGs are mainly enriched in biological processs of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism and positive regulation of cell cycle. Among them, insulin-like growth factor type 2 (Igf2) gene, which was highly reversed and down-regulated by GAS, served as the core gene linking energy metabolism, immune regulation and system development. Subsequent functional verification demonstrated that the system of Igf2 and its receptor Igf2r is one of the targets of GAS in the treatment of cardiac hypertrophy, and knocking out Igf2r can protect NRCM from cardiac hypertrophy. Conclusions: Taken together, we, for the first time, identified Igf2/Igf2r as a therapeutic target influenced by GAS in the pharmacological intervention of cardiac hypertrophy

2021-01-05 | GSE164187 | GEO

Corynoline protects Ang II-induced hypertensive heart failure by increasing PPARα and inhibiting NF-κB pathway

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

Cardiomyocyte-specific LARP6 overexpression prevents Angiotensin II-induced myocardial dysfunction and interstitial fibrosis

Project description:La ribonucleoprotein 6, Translational Regulator (LARP6), a multifunctional mRNA binding protein with well-described pro-fibrotic effects, increases type I collagen mRNA half-life, translation, and deposition in non-cardiac tissues. In the heart LARP6 is expressed in cardiomyocytes, not primarily involved in fibrosis, where its role is unknown. To investigate the role of cardiomyocyte-derived LARP6 on cardiac function and remodeling, we generated a cardiomyocyte-specific LARP6 overexpressing transgenic mouse model (LARP6-Tg). Baseline longitudinal studies up to 10 months of age revealed that constitutive overexpression of LARP6 had no significant effect on cardiac function or morphology despite inducing mild interstitial fibrosis versus wild-type littermates (WT). Subsequently, we hypothesized that cardiomyocyte-specific LARP6-Tg mice would exhibit exacerbated cardiac remodeling and dysfunction in response to hypertensive stress via angiotensin II (Ang II) infusion. Ang II (1000 ng/kg/min for 21 days) induced hypertension and cardiac hypertrophy in WT and LARP6-Tg mice of both sexes. Unexpectedly, Ang II-induced cardiac dysfunction was prevented in LARP6-Tg mice. Cardiac gene expression profiling predicted increased fibrosis and cardiomyocyte death in Ang II-treated WT mice and inhibition of cardiomyocyte death in Ang II-treated LARP6-Tg mice, versus saline-treated controls. Surprisingly, Ang II-induced interstitial fibrosis was reduced in LARP6-Tg mice and associated with attenuation of cardiomyocyte cell death and reduced myofibroblast activation. These data support a mild pro-fibrotic action of cardiomyocyte LARP6 in unstressed mice and, paradoxically, that LARP6 overexpression is sufficient to prevent Ang II-induced cardiac interstitial fibrosis and dysfunction. Sustained induction of LARP6 has therapeutic potential in hypertensive heart disease.

2025-01-31 | GSE284286 | GEO

Expression data of murine model of cardiac hypertrophy

Project description:An initial cellular change in the pathogenesis of heart failure is cardiomyocyte hypertrophy, characterized by increased cell size, enhanced protein synthesis and reactivation of fetal genes. In addition to mechanical stresses, several neurohumoral factors have been identified as potent hypertrophic agents, including angiotensin II, endothelin, and catecholamines. We used microarrays to study the gene expression during cardiac hypertrophy. Balb/c mice (6-8w) were treated with TAC, ATII infusion, and myocardial infarction. TAC model: The transverse aorta (TAC) was constricted at the upper left sternal border by ligation with a 7-silk surgical thread and 27-gauge needle, which was removed thereafter. Sham-operated controls underwent an identical procedure without TAC. At 1 week and 1month after the procedure, LV was harvested. Ang II model.: Ang II was dissolved in 0.9% NaCl at concentrations sufficient to allow an infusion rate of 2.0 mg/kg/day, known to produce hypertension and cardiac hypertrophy. Control mice received a vehicle (saline) via an osmotic minipump. At 1 week after the procedure, LV was harvested. MI model: The proximal portion of the left coronary artery was ligated using an 8-0 nylon thread. Myocardial ischemia was confirmed by the discoloration of the heart and typical ECG changes. After 30 min occlusion, the left coronary artery was reperfused by loosening the ligature. In sham-operated mice (SHAM), the pericardium was opened, but the coronary artery was not ligated. At 1 day, 1week, and 1 month after the procedure, LV was harvested.

2011-12-31 | E-GEOD-26671 | biostudies-arrayexpress

OTUD1 aggravates pathological cardiac hypertrophy through activation of PGAM5-ASK1 signaling pathways

Project description:Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.

2023-09-05 | GSE241809 | GEO

Transcription profiling of mouse hAT1R transgenic and non-transgenic C57BL/6 heart tissue

Project description:Excessive Ang II signaling through AT1R is shown to cause pathological hypertrophy. Underlying molecular mechanisms are not yet known and expression studies are not available so far. To understand hAT1R signaling, cardiac tissue, from C57BL/6 mouse over expressing hAT1R signaling, is subjected to genomic microarray studies. This data compared with the data from healthy, non transgenic C57BL/6 mouse. Experiment Overall Design: Mouse heart tissues are collected from age matched and gender matched samples. RNA is isolated using commercial kits as per the manufacturer's instructions and subjected to quality checks before experiments. cRNA preparation, pre hybridization, hybridization and post hybridization were carried out Genomics core facility, Case western reserve university. 3 chips for each category were taken for present analysis.

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Project description:Here, we performed pathological cardiac hypertrophy transcriptome analyses by using heart tissue from Sham or TAC surgery to identify the charecteric in pathological cardiac hypertrophy. In addition, through combined analysis with the aging-associated transcriptome to identify the similarity and difference between heart ageing and pathological cardiac hypertrophy.

2025-01-29 | GSE203083 | GEO

Cardiac Remodeling During Pregnancy With Metabolic Syndrome: Prologue of Pathological Remodeling

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

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