Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction
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ABSTRACT:
PROVIDER: PRJNA792555 | ENA |
REPOSITORIES: ENA
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Project description:Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyzes. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.
2021-12-30 | GSE192643 | GEO
Project description:Lionheart LincRNA Alleviates Cardiac Systolic Dysfunction under Pressure Overload
| PRJNA644194 | ENA
Project description:Aim was to investigate the effect of cardiomyocyte-specific expression of the human Relaxin Family Peptide Receptor 1 (RXFP1) in a mouse model of pressure-overload induced cardiac dysfunction (TAC). Mice overexpressing the hRXFP1 receptor (or non-transgenic controls) underwent TAC (or Sham) surgery and were followed up for 8 weeks. Heart was removed and RNA isolated from left ventricle to perform bulk RNAseq.
2024-05-23 | GSE252607 | GEO
Project description:Failure of molecular chaperones to direct the correct folding of newly synthesized proteins leads to the accumulation of misfolded proteins in cells. HSPA4 is a member of the heat shock protein 110 family (HSP110) that acts as a nucleotide exchange factor of HSP70 chaperones. We found that the expression of HSPA4 is upregulated in murine hearts subjected to pressure overload and in failing human hearts. To investigate the cardiac function of HSPA4, Hspa4 knockout (KO) mice were generated and exhibited cardiac hypertrophy and fibrosis. Hspa4 KO hearts were characterized by a significant increase in heart weight/body weight ratio, elevated expression of hypertrophic and fibrotic gene markers, and concentric hypertrophy with preserved contractile functions. Cardiac hypertrophy in Hspa4 KO hearts was associated with enhanced activation of gp130-STAT3, CaMKII, and calcineurin-NFAT signaling. Further analyses revealed a significant increase in cross sectional area of cardiomyocytes, and in expression levels of hypertrophic markers in cultured neonatal Hspa4 KO cardiomyocytes suggesting that the hypertrophy of mutant mice was a result of primary defects in cardiomyocytes. Gene expression profile in hearts of 3.5-week-old mice revealed a differentially expressed gene sets related to ion channels and stress response. Taken together, these results reveal that HSPA4 is implicated in protection against pressure overload-induced heart failure. Total RNA was extracted from heart ventricles of 3.5-week-old Hspa4+/+ and Hspa4-/- males (n = 3 mice for each genotype).
2012-10-10 | E-GEOD-32885 | biostudies-arrayexpress
Project description:Background: In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods: We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. Results: RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 vs. RV hypertrophy 334.3±30.65 vs. RV failure 165.4±36.72 pmol/(sec*ml), p<0.0001). Mitochondrial fission protein DRP1 did not change, while MFF decreased and fusion protein OPA1 decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusion: Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.
2021-03-18 | GSE152413 | GEO
Project description:Myocardial deletion of klf4 sensitizes mouse to pressure overload. In order to gain a better understanding of molecular mechanisms of such alterations, we profiled gene expression before and after 3-day of pressure overload (induced by transverse aortic constriction -TAC) in the hearts from MHC-cre (Cre) control and MHC-cre-klf4-deficient (KO) mice. 10wk old male mice was subjected to transverse aortic constriction (TAC) to induce pressure overload or sham operation as control group. After 3 days, heart was removed and total RNA was extracted from apex and subjected for array analysis. Four animals in each group.
2015-07-01 | E-GEOD-61177 | biostudies-arrayexpress
Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.
2019-07-26 | GSE121308 | GEO
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
Project description:Failure of molecular chaperones to direct the correct folding of newly synthesized proteins leads to the accumulation of misfolded proteins in cells. HSPA4 is a member of the heat shock protein 110 family (HSP110) that acts as a nucleotide exchange factor of HSP70 chaperones. We found that the expression of HSPA4 is upregulated in murine hearts subjected to pressure overload and in failing human hearts. To investigate the cardiac function of HSPA4, Hspa4 knockout (KO) mice were generated and exhibited cardiac hypertrophy and fibrosis. Hspa4 KO hearts were characterized by a significant increase in heart weight/body weight ratio, elevated expression of hypertrophic and fibrotic gene markers, and concentric hypertrophy with preserved contractile functions. Cardiac hypertrophy in Hspa4 KO hearts was associated with enhanced activation of gp130-STAT3, CaMKII, and calcineurin-NFAT signaling. Further analyses revealed a significant increase in cross sectional area of cardiomyocytes, and in expression levels of hypertrophic markers in cultured neonatal Hspa4 KO cardiomyocytes suggesting that the hypertrophy of mutant mice was a result of primary defects in cardiomyocytes. Gene expression profile in hearts of 3.5-week-old mice revealed a differentially expressed gene sets related to ion channels and stress response. Taken together, these results reveal that HSPA4 is implicated in protection against pressure overload-induced heart failure.
2012-10-10 | GSE32885 | GEO
Project description:Myocardial deletion of klf4 sensitizes mouse to pressure overload. In order to gain a better understanding of molecular mechanisms of such alterations, we profiled gene expression before and after 3-day of pressure overload (induced by transverse aortic constriction -TAC) in the hearts from MHC-cre (Cre) control and MHC-cre-klf4-deficient (KO) mice.
2015-07-01 | GSE61177 | GEO