Alterations of β-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-β1

2002 ◽  
Vol 283 (3) ◽  
pp. H1253-H1262 ◽  
Author(s):  
Stephan Rosenkranz ◽  
Markus Flesch ◽  
Kerstin Amann ◽  
Claudia Haeuseler ◽  
Heiko Kilter ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Heart Weight ◽  
Adrenergic System ◽  
Adrenergic Signaling ◽  
In Vivo Effects

Transforming growth factor-β1 (TGF-β1) promotes or inhibits cell proliferation and induces fibrotic processes and extracellular matrix production in numerous cell types. Several cardiac diseases are associated with an increased expression of TGF-β1 mRNA, particularly during the transition from stable cardiac hypertrophy to heart failure. In vitro studies suggest a link between TGF-β1 signaling and the β-adrenergic system. However, the in vivo effects of this growth factor on myocardial tissue have been poorly identified. In transgenic mice overexpressing TGF-β1 (TGF-β), we investigated the in vivo effects on cardiac morphology, β-adrenergic signaling, and contractile function. When compared with nontransgenic controls (NTG), TGF-β mice revealed significant cardiac hypertrophy (heart weight, 164 ± 7 vs. 130 ± 3 mg, P < 0.01; heart weight-to-body weight ratio, 6.8 ± 0.3 vs. 5.1 ± 0.1 mg/g, P < 0.01), accompanied by interstitial fibrosis. These morphological changes correlated with an increased expression of hypertrophy-associated proteins such as atrial natriuretic factor (ANF). Furthermore, overexpression of TGF-β1 led to alterations of β-adrenergic signaling as myocardial β-adrenoceptor density increased from 7.3 ± 0.3 to 11.2 ± 1.1 fmol/mg protein ( P < 0.05), whereas the expression of β-adrenoceptor kinase-1 and inhibitory G proteins decreased by 56 ± 9.7% and 58 ± 7.6%, respectively ( P < 0.05). As a consequence of altered β-adrenergic signaling, hearts from TGF-β showed enhanced contractile responsiveness to isoproterenol stimulation. In conclusion, we conclude that TGF-β1 induces cardiac hypertrophy and enhanced β-adrenergic signaling in vivo. The morphological alterations are either induced by direct effects of TGF-β1 or may at least in part result from increased β-adrenergic signaling, which may contribute to excessive catecholamine stimulation during the transition from compensated hypertrophy to heart failure.

Changes of β-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease

2000 ◽  
Vol 278 (6) ◽  
pp. H2076-H2083 ◽  
Author(s):  
Ulrich Schotten ◽  
Karsten Filzmaier ◽  
Britta Borghardt ◽  
Simone Kulka ◽  
Friedrich Schoendube ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
G Protein ◽  
Adrenergic System ◽  
Plasma Catecholamine ◽  
Human Heart Failure ◽  
Α Subunit ◽  
Adrenergic Signaling ◽  
G Protein Α Subunit ◽  
Catecholamine Levels

In human heart failure, desensitization of the β-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the β-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial β-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). β-Adrenoceptor density determined by [125I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein α-subunit (Gsα) measured by immunoblotting was unchanged, whereas the inhibitory G protein α-subunit (Gαi-2) was increased. In contrast, in AoSt, Gαi-2 protein was unchanged, but Gsα protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with β-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels.

Abstract 1828: Dyxin/Lmcd1 Mediates Cardiac Hypertrophy Both In Vitro And In Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Derk Frank ◽  
Robert Frauen ◽  
Christiane Hanselmann ◽  
Christian Kuhn ◽  
Rainer Will ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
The Novel ◽  
Rat Cardiomyocytes ◽  
A Genome

In order to identify new molecular mediators of cardiomyocyte hypertrophy, we performed a genome wide mRNA microarray screen of biomechanically stretched neonatal rat cardiomyocytes (NRCM). We found the novel sarcomeric LIM protein Dyxin/Lmcd1 being significantly upregulated (5.6x, p<0.001). Moreover, Dyxin was also significantly induced in several mouse models of myocardial hypertrophy including aortic banding, calcineurin overexpression and angiotensin stimulation, suggesting a potential role as a mediator of cardiac hypertrophy. To further test this hypothesis, we adenovirally overexpressed Dyxin in NRCM which potently induced cellular hypertrophy (150%, p<0.001) and the hypertrophic gene program (ANF, BNP). Consistent with an induction of calcineurin signalling, the calcineurin-responsive gene Rcan1– 4 (MCIP1.4) was found significantly upregulated (3.2x, p<0.001). Conversely, knockdown of Dyxin (−75% on protein level) via miRNA completely blunted the hypertrophic response to hypertrophic stimuli, including stretch and PE (both p<0.001). Furthermore, PE-mediated activation of calcineurin signaling (Upregulation of Rcan1– 4 by 7.3x, p<0.001) was completely blocked by knockdown of Dyxin. To confirm these results in vivo, we next generated transgenic mice with cardiac-restricted overexpression of Dyxin using the α -MHC promoter. Despite normal cardiac function as assessed by echocardiography, adult transgenic mice displayed significant cardiac hypertrophy in morphometrical analyses (3.9 vs. 3.5 mg/g LV/heart weight, n=8–11, p<0.05). This finding was supplemented by a robust induction of the hypertrophic gene program including ANF (3.7-fold, n=6, p=0.01) and α -skeletal actin (2.8-fold, n=6, p<0.05). Likewise, Rcan1– 4 was found upregulated (+112%, n=5, p<0.05), Taken together, we show that the novel sarcomeric z-disc protein Dyxin/Lmcd1 is significantly upregulated in several models of cardiac hypertrophy and potently induces cardiomyocyte hypertrophy both in vitro and in vivo. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway.

scholarly journals Loss of β-adrenergic–stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure

2016 ◽  
Vol 113 (49) ◽  
pp. E7976-E7985 ◽  
Author(s):  
Linghai Yang ◽  
Dao-Fu Dai ◽  
Can Yuan ◽  
Ruth E. Westenbroek ◽  
Haijie Yu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Troponin I ◽  
Contractile Function ◽  
Voluntary Exercise ◽  
Adrenergic Stimulation ◽  
Compensatory Mechanisms ◽  
Specific Expression ◽  
Altered Expression

L-type Ca2+ currents conducted by voltage-gated calcium channel 1.2 (CaV1.2) initiate excitation–contraction coupling in the heart, and altered expression of CaV1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the CaV1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of CaV1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.

scholarly journals Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

2004 ◽  
Vol 279 (19) ◽  
pp. 20422-20434 ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Douglas W. Leaman ◽  
Sudhiranjan Gupta ◽  
Parames Sil ◽  
David Young ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Gene Clusters ◽  
The United States ◽  
Cellular Interaction ◽  
Marker Genes ◽  
Human Heart Failure

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophyin vitro. In this report, we present data on the pathophysiological significance of myotrophinin vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophyversustransition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.

Abstract 559: Diacylglycerol Kinase-ζ Rescues Gαq-induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Takeshi Niizeki ◽  
Yasuchika Takeishi ◽  
Yo Koyama ◽  
Tatsuro Kitahara ◽  
Satoshi Suzuki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Heart Weight ◽  
Type I ◽  
Gpcr Signaling

Background: It has been reported that the expression of a constitutively active mutant of the G protein αq subunit in the hearts of transgenic mice (Gαq-TG) induces cardiac hypertrophy and lethal heart failure. Thus, the Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) catalyzes DAG and controls cellular DAG levels, and thus may act as a negative regulator of GPCR signaling. In this study, we tested the hypothesis that DGKζ rescues Gαq-TG mice from developing heart failure. Methods and Results: We generated double transgenic mice (Gαq/DGKζ-TG) with cardiac-specific overexpression of both DGKζ and constitutive active Gαq by crossing Gαq-TG mice with transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG), and the pathophysiological consequences were analyzed. DGKζ inhibited cardiac hypertrophy and progression to heart failure in Gαq-TG mice (Table ). DGKζ prevented dilatation of left ventricular dimension and reduction of left ventricular fractional shortening in Gαq-TG mice. Markedly increased left ventricular end-diastolic pressure in Gαq-TG mice was normalized in Gαq/DGKζ-TG mice. Increases in heart weight/body weight ratio and cardiomyocyte cross sectional area were attenuated in Gαq/DGKζ-TG mice. Translocation of PKC α and ε isoforms, activation of JNK and p38 MAPK induced by Gαq were attenuated by DGKζ. DGKζ reduced fibrotic changes and concomitant upregulation of fibrosis-related genes such as collagen type I and type III induced by Gαq. DGKζ improved the survival rate of Gαq-TG mice. Conclusions: These results demonstrate the first evidence that DGKζ prevents cardiac dysfunction and heart failure by activated Gαq without detectable adverse effects in in vivo hearts and suggest that DGKζ represents a novel therapeutic target for cardiac hypertrophy and heart failure. Summary of the results

Abstract 27: The Transcription Cofactor Eya4 Mediates the Development of Acquired Cardiac Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Tatjana Williams ◽  
Jost Schoenberger ◽  
Moritz Hundertmark ◽  
Peter Nordbeck ◽  
Sabine Voll ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Kinase Inhibitor ◽  
Late Onset ◽  
Heart Weight ◽  
Histone Deacetylase 2 ◽  
Transcription Cofactor ◽  
Age Dependent ◽  
Baseline Conditions

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.

scholarly journals Flavonoids Extraction from Propolis Attenuates Pathological Cardiac Hypertrophy through PI3K/AKT Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Guang-wei Sun ◽  
Zhi-dong Qiu ◽  
Wei-nan Wang ◽  
Xin Sui ◽  
Dian-jun Sui
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Biological Activities ◽  
Akt Signaling ◽  
Heart Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Wide Range

Propolis, a traditional medicine, has been widely used for a thousand years as an anti-inflammatory and antioxidant drug. The flavonoid fraction is the main active component of propolis, which possesses a wide range of biological activities, including activities related to heart disease. However, the role of the flavonoids extraction from propolis (FP) in heart disease remains unknown. This study shows that FP could attenuate ISO-induced pathological cardiac hypertrophy (PCH) and heart failure in mice. The effect of the two fetal cardiac genes, atrial natriuretic factor (ANF) andβ-myosin heavy chain (β-MHC), on PCH was reversed by FP. Echocardiography analysis revealed cardiac ventricular dilation and contractile dysfunction in ISO-treated mice. This finding is consistent with the increased heart weight and cardiac ANF protein levels, massive replacement fibrosis, and myocardial apoptosis. However, pretreatment of mice with FP could attenuate cardiac dysfunction and hypertrophyin vivo. Furthermore, the cardiac protection of FP was suppressed by the pan-PI3K inhibitor wortmannin. FP is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorder, such as fibrosis. The effects may be closely correlated with PI3K/AKT signaling. FP may be clinically used to inhibit PCH progression and heart failure.

scholarly journals p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

2013 ◽  
Vol 305 (7) ◽  
pp. H1010-H1019 ◽  
Author(s):  
Catherine L. Passariello ◽  
Marjorie Gayanilo ◽  
Michael D. Kritzer ◽  
Hrishikesh Thakur ◽  
Zoharit Cozacov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Cardiac Insufficiency ◽  
S6 Kinase ◽  
Transgenic Expression ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

scholarly journals Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

2008 ◽  
Vol 294 (6) ◽  
pp. H2889-H2897 ◽  
Author(s):  
Qianwen Wang ◽  
Rajakumar V. Donthi ◽  
Jianxun Wang ◽  
Alex J. Lange ◽  
Lewis J. Watson ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Cardiac Metabolism ◽  
Heart Weight ◽  
Acid Oxidation ◽  
Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

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