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Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension [Affymetrix]

ABSTRACT: We assigned carboxypeptidase X 2 (Cpxm2) to a genetic locus for left ventricular mass. The functional role of Cpxm2 was investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA)-salt hypertension and control conditions (SHAM). Both WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage. These changes were significantly ameliorated or even normalized (i.e. ejection fraction) in KO-DOCA animals. LV transcriptome analysis in WT, but not in KO mice, showed a molecular cardiac hypertrophy/remodeling signature with significant upregulation of 1234 transcripts including Cpxm2 in response to DOCA.

ORGANISM(S): Mus musculus

PROVIDER: GSE154321 | GEO | 2023/07/10

REPOSITORIES: GEO

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Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension [Illumina]

Project description:To identify novel targets in left ventricular (LV) hypertrophy (LVH) we initiated comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP) and Fischer (F344). Previous genetic studies in the SHRSP/F344 model confirmed the presence of a major quantitative trait locus (QTL) for LV mass on rat chromosome (RNO) 1. We assigned carboxypeptidase X 2 (Cpxm2) to a genetic locus for LV mass identified in SHRSP. We assigned carboxypeptidase X 2 (Cpxm2) to a genetic locus for left ventricular mass.

2023-07-10 | GSE154326 | GEO

RNA-sequence analysis of mouse AAA samples obtained from wild type mice and PSGL-1-/- mice induced by DOCA plus salt or not

Project description:We report the transcriptomic analysis of RNA-seq of abdominal aortas isolated from WT and PSGL-1-/- mice exposed to deoxycorticosterone acetate (DOCA) plus salt to uncover the mechanisms underlying the undefined role of PSGL-1 in abdominal aortic aneurysm (AAA)

2020-12-31 | GSE153425 | GEO

High-salt diet leads to differential gene expression in DOCA-treated mice

Project description:In the present study we made use of the (1-renin) DOCA-salt mouse model - which has been previously shown to develop cardiac and renal hypertrophy - to evaluate the direct effects of high-salt diet on cardiac function and gene expression profiling. The comparison between low-salt and high-salt DOCA-treated mice will reveal what genes are directly modulated by sodium in (normotensive) DOCA-treated mice. Previous publications: Wang Q, Hummler E, Nussberger J, Clement S, Gabbiani G, Brunner HR, Burnier M. Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of renin genes. J Am Soc Nephrol. 2002;13:1509 –1516. Wang Q, Domenighetti AA, Pedrazzini T, Burnier M. Potassium supplementation reduces cardiac and renal hypertrophy independent of blood pressure in DOCA/salt mice. Hypertension. 2005 Sep;46(3):547-54. Keywords: comparative dose-response treatment (2 groups)

2007-01-01 | GSE5946 | GEO

Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension

Project description:Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral nucleus (RVLM). Overactivation of bulbospinal neurons RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the “maintenance” phase with a maximal peak at 13 days on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems.

2023-09-14 | GSE235234 | GEO

Immune profiling of murine cardiac leukocytes identifies Trem2 as a novel mediator of hypertensive heart failure

Project description:Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodeling. Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. CITE-Seq analysis of cardiac immune cells reveals an altered abundance and/or transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including upregulation of Trem2, which was also recently implicated in obesity and atherosclerosis. The role of macrophage Trem2 in cardiac remodeling, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls, and Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programs. Furthermore, we found that plasma levels of soluble TREM2 are elevated in human heart failure. Together, our data suggest a novel cardioprotective role for macrophage Trem2 in cardiac remodeling and heart failure and provide an atlas for the identification of additional targets that can lead to improved diagnostic and therapeutic strategies for HFpEF.

2023-05-01 | GSE211166 | GEO

Expression data from kidney cortex of control and transgenic sgk1 mice under DOCA/NaCl treatment

Project description:Serum and glucocorticoid-induced kinase 1 (SGK1) regulates blood pressure and has been implicated in inflammation and fibrosis. We have tested whether increased SGK1 activity potentiates mineralocorticoid/NaCl-induced hypertension and kidney injury. To that end we have used a transgenic mouse model with increased SGK1 activity (Tg.sgk1). This data set consists on transcriptomic analysis of kidney cortex samples to obtain differential gene expression due to excess SGK1 activity between wild type or Tg.sgk1 animals that were uninephrectomized and then treated with DOCA/NaCl

2020-08-31 | GSE148880 | GEO

Gene expression profiling in Wistar male rat left ventricle with chronic and severe aortic valve regurgitation

Project description:Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV) which results in dilation, eccentric hypertrophy and eventually loss of function. Little is known about the impact of AR on LV gene expression. We therefore conducted a gene expression profiling study in the LV of male Wistar rats with chronic (9 months) and severe AR. Five male Wistar rats had one or two aortic valve leaflets punctured with a catheter under echocardiographic guidance in order to induce severe regurgitation (>65% of blood regurgitating during diastole from the aorta to the left ventricle). Five additional rats were sham-operated. The animals were sacrificed 9 months after the procedure and their left ventricle collected for RNA extraction and microarray analysis.

2010-04-13 | E-GEOD-17050 | biostudies-arrayexpress

Cathepsin A contributes to left ventricular remodeling by degrading the antioxidant enzyme extracellular superoxide dismutase

Project description:In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM-remodeling and left ventricular (LV) dysfunction. This study aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA (5-fold decreased abundance; p=0.0001). In vitro, cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein. EC-SOD protein was expressed and secreted only by cardiac fibroblasts. Cardiomyocyte-specific over-expression of CatA and increased activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43% (p<0.001). Loss of EC-SOD-mediated anti-oxidative protection resulted in accumulation of superoxide radicals (WT: 4.54±1.2 vs. CatA-TG: 8.62±2.3µmol/mg tissue/min; p=0.0012), increased inflammation, myocyte hypertrophy (WT: 19.8±1.0 vs. CatA-TG: 21.9±1.8µm; p=0.024), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and pro-fibrotic marker genes, without effecting intracellular detoxifying proteins. In CatA-TG mice LV interstitial fibrosis formation was enhanced by 19% (p=0.028) and type I/type III collagen ratio was shifted towards higher abundance of collagen I fibers (p=0.026). Cardiac remodeling in CatA-TG was accompanied by increased LV weight/body weight and LV enddiastolic volume (WT: 50.8±5.8 vs. CatA-TG: 61.9±6.2 µl; p=0.018). Thus, in the heart CatA-mediated reduction of EC-SOD protein contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling and inflammation. This implicates CatA as a potential therapeutic target to prevent ventricular remodeling.

2020-07-10 | PXD019895 | Pride

Mus musculus

Project description:Expression data from WT and RGS5 KO mice treated with DOCA/salt

| PRJNA350226 | ENA

The effects of Arginase 2 (Arg2) knockout on chronic hypoxia-induced pulmonary hypertension

Project description:Increased arginase 2 protein expression is associated with endothelial dysfunction and pulmonary hypertension, likely by impairing NO production secondary to substrate availability. Hypoxia induces arginase 2 protein expression contributing to pulmonary vascular cell proliferation. Non-specific arginase inhibitors have been shown to prevent experimental pulmonary hypertension in animal models. RNA was isolated from whole lung tissue from adult (12-14 weeks) arginase 2 wild type and KO mice exposed to 21% O2 or 10% O2 for 28 days. Animals were sacrificed and the lungs collected and stored at -80°C . Total RNA was isolated with Trizol and used for RNA-seq. RNA-seq results indicate notable differentially expressed gene transcripts were evident in the Arg2 WT and Arg2 KO lungs. There were 25 unique transcripts identified (>2-fold change, p < 0.001) between the normoxia and hypoxia-exposed Arg2 WT. Interestingly, there was significantly greater differences in the Arg2 KO mice exposed to hypoxia compared to normoxia, with 188 unique transcripts (>2-fold change, p < 0.001) identified by RNA seq.

2020-05-01 | GSE131425 | GEO

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