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Celecoxib prevents pressure overload-induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress.

ABSTRACT: To explore the effects of celecoxib on pressure overload-induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body-weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib-induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF-κB pathway and inhibition of oxidative stress via increases in nuclear factor E2-related factor-2-mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload-induced CH by reducing apoptosis, inflammation and oxidative stress.

SUBMITTER: Zhang C

PROVIDER: S-EPMC4717861 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Tomoregulin-1 prevents cardiac hypertrophy after pressure overload in mice by inhibiting TAK1-JNK pathways.

Project description:Cardiac hypertrophy is associated with many forms of heart disease, and identifying important modifier genes involved in the pathogenesis of cardiac hypertrophy could lead to the development of new therapeutic strategies. Tomoregulin-1 is a growth factor that is primarily involved in embryonic development and adult central nervous system (CNS) function, and it is expressed abnormally in a variety of CNS pathologies. Tomoregulin-1 is also expressed in the myocardium. However, the effects of tomoregulin-1 on the heart, particularly on cardiac hypertrophy, remains unknown. The aim of the study is to examine whether and by what mechanism tomoregulin-1 regulates the development of cardiac hypertrophy induced by pressure overload. In this study, we found that tomoregulin-1 was significantly upregulated in two cardiac hypertrophy models: cTnT(R92Q) transgenic mice and thoracic aorta constriction (TAC)-induced cardiac hypertrophy mice. The transgenic overexpression of tomoregulin-1 increased the survival rate, improved the cardiac geometry and functional parameters of echocardiography, and decreased the degree of cardiac hypertrophy of the TAC mice, whereas knockdown of tomoregulin-1 expression resulted in an opposite phenotype and exacerbated phenotypes of cardiac hypertrophy induced by TAC. A possible mechanism by which tomoregulin-1 regulates the development of cardiac hypertrophy in TAC-induced cardiac hypertrophy is through inhibiting TGF? non-canonical (TAK1-JNK) pathways in the myocardium. Tomoregulin-1 plays a protective role in the modulation of adverse cardiac remodeling from pressure overload in mice. Tomoregulin-1 could be a therapeutic target to control the development of cardiac hypertrophy.

| S-EPMC4527297 | biostudies-literature

Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction.

Project description:AimsClinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)].Methods and resultsWe assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha.ConclusionDietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.

| S-EPMC2721645 | biostudies-literature

Pressure overload cardiac hypertrophy

Project description:Expression profiling of hearts from FVB males subjected to cardiac pressure overload by transverse aortic constriction (TAC). TAC performed on 8-10 weeks month old males and females. Hearts examined 30 weeks after surgery. Keywords: ordered

2005-06-29 | GSE2459 | GEO

Loss of Bmx nonreceptor tyrosine kinase prevents pressure overload-induced cardiac hypertrophy.

Project description:Bmx nonreceptor tyrosine kinase has an established role in endothelial and lymphocyte signaling; however, its role in the heart is unknown. To determine whether Bmx participates in cardiac growth, we subjected mice deficient in the molecule (Bmx knockout mice) to transverse aortic constriction (TAC). In comparison with wild-type mice, which progressively developed massive hypertrophy following TAC, Bmx knockout mice were resistant to TAC-induced cardiac growth at the organ and cell level. Loss of Bmx preserved cardiac ejection fraction and decreased mortality following TAC. These findings are the first to demonstrate a necessary role for the Tec family of tyrosine kinases in the heart and reveal a novel regulator (Bmx) of pressure overload-induced hypertrophic growth.

| S-EPMC2735252 | biostudies-literature

Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.

Project description:For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (betaAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by betaAR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.

| S-EPMC1464895 | biostudies-other

Pimobendan attenuates pressure overload-induced myocardial hypertrophy by inhibiting the MAPKs pathway

Project description:Background: Although myocardial hypertrophy is an essential component of heart’s response to many forms of stress, prolonger excessive hypertrophy contributes importantly to the pathogenesis of heart disease. The pimobendan is a drug that both inhibits phosphodiesterase 3 (PDE3) and acts as a calcium sensitizer, which has been used to treat heart failure. The effects of pimobendan on myocardial hypertrophy is controversial. Objective: This study aims to evaluate the therapeutic effect of pimobendan on myocardial hypertrophy. Methods: Mice were treated with low oral doses of pimobendan (1mg/kg/d) for 4 weeks after transaortic constriction. Heart structure and function was assessed using ultrasound, hemodynamic measurements and histology combined with biochemical assessments of myocardial hypertrophy. We also examined the effects of pimobendan (100 µM) on hypertrophy in cultured neonatal rat cardiomyocytes (NRCMs) induced by 50 µM phenylephrine (PE). Results: The doses pimobendan used in our studies had no effect on baseline contractility. Nevertheless, pimobendan administration of mice subjected to TAC decreased heart weights (normalized to either tibia length or body weight) ventricular wall thickness, cardiomyocyte sizes, myocardial fibrosis and the levels of a number of key myocardial hypertrophy markers (WHICH ONES). In cultured neonatal cardiomyocytes, pimobendan attenuated the PE-induced hypertrophy. In both hypertrophy models pimobendan reduced the phosphorylation levels of several essential proteins in the MAPK pathway, PI3K-AKT pathway, and calcineurin signaling pathway. Conclusion: Low pimobendan may attenuate myocardial hypertrophy. Although the underlying mechanisms remain to be elucidated, the MAPK pathway is likely to play a role.

2023-07-01 | GSE182501 | GEO

Pressure-Overload Induced Cardiac Hypertrophy

Project description:Aortic banding is an excellent model system to evaluate the process of development of left ventricular hypertrophy in response to hemodynamic stress. The Affymetrix GeneChip MgU74Av1 was used to analyze expression profiles of mice at different time points after surgical intervention for pressure-overload induced hypertrophy. More information about this model may be obtained at http://cardiogenomics.med.harvard.edu/groups/proj1/pages/band_home.html Keywords = Pressure overload, cardiac hypertrophy Keywords: time-course

2002-07-30 | GSE76 | GEO

Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway.

Project description:Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit (p-eIF2)-?, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal (0.5 mg·kg-1·day-1) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

| S-EPMC5303890 | biostudies-literature

SERPINA3K prevents oxidative stress induced necrotic cell death by inhibiting calcium overload.

Project description:BackgroundSERPINA3K, an extracellular serine proteinase inhibitor (serpin), has been shown to have decreased levels in the retinas of diabetic rats, which may contribute to diabetic retinopathy. The function of SERPINA3K in the retina has not been investigated.Methodology/principal findingsThe present study identified a novel function of SERPINA3K, i.e. it protects retinal cells against oxidative stress-induced cell death including retinal neuronal cells and Müller cells. Flow-cytometry showed that the protective effect of SERPINA3K on Müller cells is via reducing oxidation-induced necrosis. Measurements of intracellular calcium concentration showed that SERPINA3K prevented the intracellular calcium overload induced by H(2)O(2). A similar protective effect was observed using a calcium chelator (BAPTA/AM). Further, SERPINA3K inhibited the phosphorylation of phospholipase C (PLC)-gamma1 induced by H(2)O(2). Likewise, a specific PLC inhibitor showed similar protective effects on Müller cells exposed to H(2)O(2). Furthermore, the protective effect of SERPINA3K was attenuated by a specific PLC activator (m-3M3FBS). Finally, in a binding assay, SERPINA3K displayed saturable and specific binding on Müller cells.Conclusion/significanceThese results for the first time demonstrate that SERPINA3K is an endogenous serpin which protects cells from oxidative stress-induced cells death, and its protective effect is via blocking the calcium overload through the PLC pathway. The decreased retinal levels of SERPINA3K may represent a new pathogenic mechanism for the retinal Müller cell dysfunction and neuron loss in diabetes.

| S-EPMC2605247 | biostudies-literature

Gentisic acid prevents the transition from pressure overload-induced cardiac hypertrophy to heart failure.

Project description:We previously reported that gentisic acid attenuates cardiac hypertrophy and fibrosis in transverse aortic constriction (TAC)-induced cardiac hypertrophy. Here, we examined whether gentisic acid prevents the development of heart failure. Heart failure was induced in mice via chronic TAC. Mice were administered the vehicle, gentisic acid (10 and 100?mg?kg-1?day-1), or bisoprolol (0.5?mg?kg-1?day-1) orally for 3 weeks, beginning 3 weeks after TAC. After oral administration of gentisic acid (2000 mg?kg-1), no significant differences in organ weight, histology, or analyzed serum and hematological parameters were observed between female mice in the control and gentisic acid-treated groups. Gentisic acid administration inhibited cardiac dysfunction in a dose-dependent manner, and reduced cardiac hypertrophy and fibrosis, as was revealed via western blotting, quantitative real-time PCR, and Masson's trichrome staining. Gentisic acid dose-dependently reduced the expression of fibrosis marker genes, suppressed the renin-angiotensin-aldosterone system, and reduced lung size and pulmonary vascular remodeling. Our data indicate that gentisic acid prevents cardiac hypertrophy, fibrosis, cardiac dysfunction, and pulmonary pathology in TAC-induced heart failure. These findings suggest that supplementation with gentisic acid may provide an advantage in preventing the progression from cardiac hypertrophy to heart failure.

| S-EPMC6395621 | biostudies-literature

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