Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling.
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ABSTRACT:
SUBMITTER: Peng J
PROVIDER: S-EPMC5505950 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLeft ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload.Methods and resultsPTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice.ConclusionThe local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.
| S-EPMC3553104 | biostudies-literature
Project description:This study examined whether endogenous extracellular adenosine acts to facilitate the adaptive response of the heart to chronic systolic overload. To examine whether endogenous extracellular adenosine can protect the heart against pressure-overload-induced heart failure, transverse aortic constriction was performed on mice deficient in extracellular adenosine production as the result of genetic deletion of CD73. Although there was no difference in left ventricular size or function between CD73-deficient mice (knockout [KO] mice) and wild-type mice under unstressed conditions, aortic constriction for 2 or 4 weeks induced significantly more myocardial hypertrophy, left ventricular dilation, and left ventricular dysfunction in KO mice compared with wild-type mice. Thus, after 2 weeks of transverse aortic constriction, left ventricular fractional shortening decreased to 27.4+/-2.5% and 21.9+/-1.7% in wild-type and KO mice, respectively (P<0.05). Consistent with a role of adenosine in reducing tissue remodeling, KO mice displayed increased myocardial fibrosis and myocyte hypertrophy compared with wild-type mice. Furthermore, adenosine treatment reduced phenylephrine-induced cardiac myocyte hypertrophy and collagen production in cultured neonatal rat cardiac myocytes and cardiac fibroblasts, respectively. Consistent with a role for adenosine in modulating cardiomyocyte hypertrophy, KO mice demonstrated increased activation of mammalian target of rapamycin signaling, accompanied by higher expression of the hypertrophy marker atrial natriuretic peptide. Conversely, the adenosine analogue 2-chloro-adenosine significantly reduced cell size, mammalian target of rapamycin/p70 ribosomal S6 kinase activation, and atrial natriuretic peptide expression in cultured neonatal cardiomyocytes. These data demonstrate that CD73 helps to preserve cardiac function during chronic systolic overload by preventing maladaptive tissue remodeling.
| S-EPMC2398698 | biostudies-literature
Project description:Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)-induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload.
| S-EPMC2429959 | biostudies-literature
Project description:AMP activated protein kinase (AMPK) plays an important role in regulating myocardial metabolism and protein synthesis. Activation of AMPK attenuates hypertrophy in cultured cardiac myocytes, but the role of AMPK in regulating the development of myocardial hypertrophy in response to chronic pressure overload is not known. To test the hypothesis that AMPKalpha2 protects the heart against systolic overload-induced ventricular hypertrophy and dysfunction, we studied the response of AMPKalpha2 gene deficient (knockout [KO]) mice and wild-type mice subjected to 3 weeks of transverse aortic constriction (TAC). Although AMPKalpha2 KO had no effect on ventricular structure or function under control conditions, AMPKalpha2 KO significantly increased TAC-induced ventricular hypertrophy (ventricular mass increased 46% in wild-type mice compared with 65% in KO mice) while decreased left ventricular ejection fraction (ejection fraction decreased 14% in wild-type mice compared with a 43% decrease in KO mice). AMPKalpha2 KO also significantly exacerbated the TAC-induced increases of atrial natriuretic peptide, myocardial fibrosis, and cardiac myocyte size. AMPKalpha2 KO had no effect on total S6 ribosomal protein (S6), p70 S6 kinase, eukaryotic initiation factor 4E, and 4E binding protein-1 or their phosphorylation under basal conditions but significantly augmented the TAC-induced increases of p-p70 S6 kinase(Thr389), p-S6(Ser235), and p-eukaryotic initiation factor 4E(Ser209). AMPKalpha2 KO also enhanced the TAC-induced increase of p-4E binding protein-1(Thr46) to a small degree and augmented the TAC-induced increase of p-Akt(Ser473). These data indicate that AMPKalpha2 exerts a cardiac protective effect against pressure-overload-induced ventricular hypertrophy and dysfunction.
| S-EPMC2760829 | biostudies-literature
Project description:Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.
| S-EPMC5886579 | biostudies-literature
Project description:Recent studies demonstrated that metabolic syndrome and cardiovascular diseases could be elicited by developmental programming, which is regulated by prenatal nutritional and environmental stress. In this study, we utilized a rat model to examine the effect of excessive maternal fructose intake during pregnancy and lactation on cardiac development and progression of pressure overload-induced cardiac hypertrophy in offspring. Transverse aortic constriction (TAC) was performed on 3-month-old male offspring to induce ventricular pressure overload. Four weeks post-TAC, echocardiographic assessment as well as histopathological and biochemical examinations were performed on the myocardium of the offspring. Echocardiographic and gross examinations showed that heart weight, interventricular septal thickness in diastole (IVD; d), and left ventricular posterior wall thickness in diastole (LVPW; d) were elevated in offspring with TAC and further increased by maternal fructose exposure (MFE). However, the left ventricular ejection function was not significantly affected. Myocardial histopathological examination revealed that the indices of fibrosis and oxidative stress were higher in offspring with MFE and TAC than those in animals receiving either treatment. Molecular examinations on the myocardium demonstrated an MFE-induced upregulation of p38-MAPK signaling. Next generation sequence (NGS) analysis indicated a modulation of the expression levels of several cardiac hypertrophy-associated genes, including GPR22, Myh7, Nppa, P2RX4, and Npy by MFE. Subsequent RT-PCR indicated that MFE regulated the expression levels of genes responsive to cardiac hypertrophy (i.e., Myh-7, ANP) and oxidative stress (i.e., GR, GPx, and NQO-1). In conclusion, MFE during pregnancy and lactation modulated myocardial gene expression, increased oxidative stress, and exacerbated ventricular pressure overload-induced cardiac remodeling in rat offspring.
| S-EPMC8467570 | biostudies-literature
Project description:Numerous experimental studies have supported the evidence that 2-methoxyestradiol (2?ME) is a biologically active metabolite that mediates multiple effects on the cardiovascular system, largely independent of the estrogen receptor. 2?ME is a major cytochrome P450 1B1 (CYP1B1) metabolite and has been reported to have vasoprotective and anti-inflammatory actions. However, whether 2?ME would prevent cardiac hypertrophy induced by abdominal aortic constriction (AAC) has not been investigated yet. Therefore, the overall objectives of the present study were to elucidate the potential antihypertrophic effect of 2?ME and explore the mechanism(s) involved. Our results showed that 2?ME significantly inhibited AAC-induced left ventricular hypertrophy using echocardiography. The antihypertrophic effect of 2?ME was associated with a significant inhibition of CYP1B1 and mid-chain hydroxyeicosatetraenoic acids. Based on proteomics data, the protective effect of 2?ME is linked to the induction of antioxidant and anti-inflammatory proteins in addition to the modulation of proteins involved in myocardial energy metabolism. In vitro, 2?ME has shown a direct antihypertrophic effect through mitogen-activated protein kinases- and nuclear factor-?B-dependent mechanisms. The present work shows a strong evidence that 2?ME protects against left ventricular hypertrophy. Our data suggest the potential of repurposing 2?ME as a selective CYP1B1 inhibitor for the treatment of heart failure.
| S-EPMC5807528 | biostudies-literature
Project description:BackgroundElevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.MethodsWe performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout (Etv1f/fMlc2aCre/+).ResultsUsing the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1, ERBB4, SCN5A, and GJA5 levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4, Etv1, Scn5a, and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1, and numerous collagen genes. Etv1f/fMlc2aCre/+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1f/fMlc2aCre/+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes.ConclusionsETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.
| S-EPMC8449308 | biostudies-literature
Project description:Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD+ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.
| S-EPMC6355077 | biostudies-literature
Project description:This study examined the impact of septal flattening on left ventricular (LV) torsion in patients with precapillary pulmonary hypertension (PH). Fifty-two patients with proven precapillary PH and 13 healthy controls were included. Ventricular function was assessed including 4D-measurements, tissue velocity imaging, and speckle tracking analysis. Increased eccentricity index (1.39 vs. 1.08, p<0.001), systolic pulmonary artery pressure (64 vs. 29mmHg, p<0.001) and right ventricular Tei index (0.55 vs. 0.28, p = 0.007), and reduced tricuspid annular plane systolic excursion (19.0 vs. 26.5mm, p<0.001) were detected in PH patients as compared to controls. With increasing eccentricity of left ventricle, LV torsion was both decreased and delayed. Torsion rate paralleled this pattern of change during systole, but not during diastole. In conclusion, right ventricular pressure overload directly affects LV torsion mechanics. The echocardiographic methodology applied provides novel insights in the interrelation of right- and left ventricular function.
| S-EPMC7217436 | biostudies-literature