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Science China. Life sciences 10/2012; 55(10):841-2. · 2.02 Impact Factor
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ABSTRACT: Beta-adrenoceptors (ARs), members of the G protein-coupled receptor (GPCR) superfamily, play a key role in the rapid regulation of myocardial function. Meanwhile, chronic catecholamine stimulation of adrenoceptors has been proved to be involved in the adverse myocardial remodeling, including cardiac hypertrophy, fibrosis, and apoptosis, which finally develop into heart failure. In the clinical situation, sympathetic hyperactivity is a key factor in the development of heart failure, and beta-blockers greatly improve the outcome of the disease. However, heart failure is still one of the leading causes of death. Therefore, a full understanding of the mechanism of beta-AR-mediated cardiac remodeling could indicate more targets for treating heart failure. This review summarizes a number of important signaling pathways involved in the process of cardiac pathological remodeling under chronic adrenergic stimulation.
Frontiers in bioscience (Elite edition) 01/2012; 4:1625-37.
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Jian Wang,
Yao Song,
Yan Zhang, Han Xiao,
Qiang Sun,
Ning Hou,
Shuilong Guo,
Youliang Wang,
Kaiji Fan,
Dawei Zhan,
Lagabaiyila Zha,
Yang Cao,
Zhenhua Li,
Xuan Cheng,
Youyi Zhang,
Xiao Yang
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ABSTRACT: Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.
Cell Research 08/2011; 22(3):516-27. · 8.19 Impact Factor
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Jian Wang,
Yao Song,
Yan Zhang, Han Xiao,
Qiang Sun,
Ning Hou,
Shuilong Guo,
Youliang Wang,
Kaiji Fan,
Dawei Zhan,
Lagabaiyila Zha,
Yang Cao,
Zhenhua Li,
Xuan Cheng,
Youyi Zhang,
Xiao Yang
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ABSTRACT: Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.Keywords: microRNA; cardiac hypertrophy; PPAR-γ; transgenic mouse; therapeutic target
Cell Research 08/2011; 22(3):516-527. · 8.19 Impact Factor
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ABSTRACT: To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.
Wild type and AMPKα2 knockout (AMPKα2⁻/⁻) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg⁻¹·d⁻¹) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting.
Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2⁻/⁻ mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2⁻/⁻ mice.
Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.
Acta Pharmacologica Sinica 05/2011; 32(7):879-87. · 1.95 Impact Factor
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ABSTRACT: 1. The purpose of the present study was to evaluate differences in the AMP-activated protein kinase (AMPK) phosphorylation sites in cardiac hypertrophy induced by L-thyroxine and angiotensin (Ang) II. 2. Cardiac hypertrophy was induced in wild-type and AMPKalpha2-knockout mice by treatment with 1 mg/kg, i.p., thyroxine or 1.44 mg/kg per day AngII for 14 days. The phenotype of the hypertrophy was evaluated using echocardiographic measurements and histological analyses. The phosphorylation of AMPK at alpha-Ser(485/491) and alpha-Thr(172) was determined by western blot analysis. 3. In wild-type mice, the phosphorylation of AMPKalpha-Ser(485/491) was significantly elevated in the AngII-treated group, but not in the thyroxine-treated group, compared with the vehicle control group. In contrast, the phosphorylation of AMPKalpha-Thr(172) was significantly increased by thyroxine, but not AngII, treatment compared with the vehicle control group. Furthermore, knockout of the AMPKalpha2 subunit abolished phosphorylation at the alpha-Ser(485/491) site and significantly suppressed phosphorylation at the alpha-Thr(172) site, resulting in alleviation of thyroxine- but not AngII-induced hypertrophy. 4. In conclusion, L-thyroxine and AngII induce the phosphorylation of distinct sites of AMPK in cardiac hypertrophy. Phosphorylation of AMPK alpha-Thr(172) may contribute to thyroxine-induced cardiac hypertrophy.
Clinical and Experimental Pharmacology and Physiology 05/2010; 37(9):919-25. · 1.85 Impact Factor
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ABSTRACT: 1. The mouse is the preferred species for gene targeting as a tool for research into the heart and heart development. The developmental features of the geometry and function of the heart in young mice are not well defined and cardiac functional responses following stimulation of beta-adrenoceptors have not been investigated. 2. Using the VisualSonic (Toronto, ON, Canada) high-resolution ultrasound system, we investigated male C57BL/6 mice at 0.5-18 weeks of age. Echocardiography was performed at baseline and repeated after administration of the beta-adrenoceptor agonist isoproterenol (4 microg/kg). 3. The geometry of the left ventricle became mature 2 weeks after birth. A significant decline in left ventricular contractile function occurred at 2-3 weeks of age. 4. Inotropic and chronotropic responses to isoproterenol were significantly weaker in mice at a weaning age < 2 weeks compared with adult mice (heart rate increment 3 +/- 3% vs 32 +/- 4%, respectively; fractional shortening increment 19 +/- 5% vs 78 +/- 8%, respectively; P < 0.001). 5. In conclusion, significant changes occur in mice from birth until weaning with respect to the topography, function and beta-adrenoceptor responsiveness of the heart. The results of the present study provide a reference point for future studies in genotyping cardiac function during the postnatal phase in genetically engineered mice.
Clinical and Experimental Pharmacology and Physiology 04/2010; 37(8):826-32. · 1.85 Impact Factor
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ABSTRACT: The mechanism of the cardioprotective action of metformin is incompletely understood. We determined the role of metformin in cardiac fibrosis and investigated the mechanism.
Ten-week-old male mice (C57BL/6) were subjected to left ventricular pressure overload by transverse aortic constriction. Mice received metformin (200 mg/kg/day) or normal saline for 6 weeks. Metformin inhibited cardiac fibrosis (fibrosis area/total heart area: 0.6 +/- 0.3 vs. 3.6 +/- 0.9%, P < 0.01) induced by pressure overload and improved cardiac diastolic function (left ventricular end-diastolic pressure: 5.2 +/- 0.9 vs. 11.0 +/- 1.6 mmHg, P < 0.05). Metformin inhibited the pressure overload-induced transforming growth factor (TGF)-beta(1) production in mouse hearts and the TGF-beta(1)-induced collagen synthesis in cultured adult mouse cardiac fibroblasts (CFs). Metformin suppressed the phosphorylation of Smad3 in response to TGF-beta(1) in CFs. Metformin also inhibited the nuclear translocation and transcriptional activity of Smad3 in CFs.
Metformin inhibited cardiac fibrosis induced by pressure overload in vivo and inhibited collagen synthesis in CFs probably via inhibition of the TGF-beta(1)-Smad3 signalling pathway. These findings provide a new mechanism for the cardioprotective effects of metformin.
Cardiovascular research 03/2010; 87(3):504-13. · 5.80 Impact Factor
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ABSTRACT: 1. In the present review, we focus on the genetic mouse models for transforming growth factor (TGF)-beta signalling, which have aided our understanding on the role of the TGF-beta signalling pathway in cardiac hypertrophy/fibrosis and the molecular mechanisms involved. 2. Knockout of TGF-beta is embryonic lethal, indicating that TGF-beta signalling plays an important role in embryonic development. In order to avoid this defect, many mouse strains with cardiac-specific targeted genes in TGF-beta signalling have been developed. 3. The TGF-beta family signalling pathway includes Smad-dependent and -independent pathways. 4. Investigations using the genetic mouse models have confirmed and uncovered the involvement of the TGF-beta/TGF-beta-activated kinase 1 (TAK1) pathway in the development of cardiac hypertrophy and fibrosis. Although the downstream cascade of TAK1-induced cardiac hypertrophy remains only partially defined, recent research indicates that the TGF-beta/TAK1/p38 pathway is involved in cardiac fibrosis 5. Smad-dependent signalling may not be involved in, or may even be inhibitory for, cardiac hypertrophy.
Clinical and Experimental Pharmacology and Physiology 04/2008; 35(3):335-41. · 1.85 Impact Factor
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ABSTRACT: To compare the different expressions of cardiac inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta(IL-1beta), interleukin-6 (IL-6) in two types of cardiac hypertrophy rat models induced by volume overload and pressure overload.
Volume overload-induced cardiac hypertrophy was established by abdominal aortacaval fistula (ACF) and pressure overload-induced cardiac hypertrophy was developed by constriction of aorta (CA). Heart weight measurement and histological examination were performed 1 week or 2 weeks after the operation respectively. The cytokine expression was measured by enzyme linked immunosorbent assay.
All the operated groups developed cardiac hypertrophy. The left ventricular fractional shortening of each operated group had no significant difference with the sham-operated groups respectively. As far as the total amount of each cytokine in left ventricular myocardium was concerned, compared to the sham-operated groups, IL-6 and IL-1beta both increased significantly in CA groups [IL-6(23 722+/-8 671)pg vs (17 693+/-5 705)pg,P<0.05 ;IL-1beta(335+/-95)pg vs (159+/-99) pg,P<0.01].There was no difference of TNF-alpha between operated and sham-operated groups in ACF or CA groups .
The contents of IL-6 and IL-1beta in myocardium increased in pressure overload-induced cardiac hypertrophy.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 12/2007; 39(6):570-5.
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ABSTRACT: To investigate the effects of beta-adrenoceptor agonist isoproterenol(ISO) on lipopolysaccharide(LPS) induced inflammatory cytokine-tumor necrosis factor-alpha(TNF-alpha) and interleukin-6(IL-6)] in monocytes from essential hypertensive patients (Stage I).
Monocytes were isolated from 17 healthy volunteers and 6 hypertensive patients' venus blood, and the monocytes were cultured with LPS (0.2 microg/L) and ISO. The concentrations of TNF-alpha and IL-6 in the cultured supernatant were measured with enzyme-linked immunosorbent assays.
(1) TNF-alpha production induced by LPS in monocytes from hypertensive group were higher than those from control group [(1,897+/-393) ng/L vs. (975+/-473) ng/L, P<0.01]. But the differences of IL-6 production were not significant between the two groups [(5,532+/-796) ng/L vs. (6,092+/-2 249) ng/L, P>0.05]. (2) ISO inhibited extracellular TNF-alpha production induced by LPS in a dose-dependent manner. The inhibitory effects were ameliorated by beta-adrenoceptor antagonist propranolol. In contrast, ISO had no effect on the production of IL-6 induced by LPS. The difference of inhibitory effects of ISO on TNF-alpha production was not statistically significant between hypertensive group and healthy control group (P>0.05).
beta-adrenergic activation inhibits TNF-alpha (but not IL-6) production induced by LPS in monocytes. The inhibitory effects were not different between early staged hypertensive patients and healthy subjects.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 12/2007; 39(6):581-6.
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ABSTRACT: As we previously reported, cAMP and p38 MAPK instead of protein kinase A were involved in beta-adrenergic receptor (beta-AR)-mediated interleukin-6 (IL-6) production in mouse cardiac fibroblasts. Besides kinases, phosphatases may also be involved in IL-6 gene regulation. To study the role of protein tyrosine phosphatases (PTPs) in beta-AR-mediated IL-6 production, we selected the most widely used PTP inhibitor, phenylarsine oxide (PAO). We found that PAO dose-dependently inhibited the IL-6 release in response to beta-AR agonist isoproterenol (ISO) in mouse cardiac fibroblasts. This effect was probably due to the inhibition of PTPs, resulting in increased tyrosine phosphorylation, since genistein, an inhibitor of protein tyrosine kinases further potentiated ISO-induced IL-6 production and could partially reverse the inhibitory effect of PAO. PAO also significantly inhibited the IL-6 production by forskolin, an adenylyl cyclase (AC) activator. Furthermore, PAO dose-dependently inhibited the increased cAMP accumulation by either ISO or forskolin and suppressed the phosphorylation of CREB, an important transcriptional factor for IL-6 gene expression. But PAO did not affect the activation of p38 MAPK by ISO. Although PAO was also reported to inhibit NADPH oxidase, the inhibition of NADPH oxidase by its specific inhibitor, diphenylene iodonium (DPI) could not suppress beta-AR-mediated IL-6 production, suggesting that NADPH oxidase may not contribute to the inhibitory effect of PAO on IL-6 production. To our knowledge, this is the first report that PAO can inhibit ISO-induced IL-6 expression and CREB phosphorylation, demonstrating that PTPs may negatively regulate beta-AR-mediated IL-6 production. This study may also further our understanding of beta-AR signaling and provide potential therapeutic targets for the treatment of heart diseases.
Biochemical and Biophysical Research Communications 02/2007; 352(3):744-9. · 2.48 Impact Factor
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ABSTRACT: We describe a patient with acute myeloid leukemia (AML) who had a deletion of chromosome 22 at q11 as a sole chromosomal abnormality, resulting in the karyotype 46,XY,del(22)(q11). Southern blot analysis showed no bcr rearrangement and fluorescence in situ hybridization indicated no juxtaposition of c-abl. This study indicates that molecular events other than bcr rearrangement and c-abl juxtaposition were involved in leukemogenesis in this patient. We hypothesize that a tumor suppressor candidate gene may be located on the long arm of chromosome 22; its loss may lead to malignant transformation.
Cancer Genetics and Cytogenetics 07/1993; · 1.39 Impact Factor
