Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor

2001 ◽  
Vol 280 (4) ◽  
pp. H1782-H1792 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Jianyuan Chai ◽  
Pamela Sheridan ◽  
Koichiro Nagano ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Response Factor ◽  
Serum Response

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac α-actin, skeletal α-actin, α-myosin heavy chain (α-MHC), and β-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

Model of functional cardiac aging: young adult mice with mild overexpression of serum response factor

2003 ◽  
Vol 285 (3) ◽  
pp. R552-R560 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Maxwell C. Furr ◽  
Ying Zhong ◽  
Jeanne Y. Wei
Keyword(s):  
Transgenic Mice ◽  
Serum Response Factor ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Diastolic Filling ◽  
Response Factor ◽  
Adult Mice ◽  
Altered Gene ◽  
And Function ◽  
Serum Response

Serum response factor (SRF) is an important transcription factor that may have a role in the maintenance of cardiac structure and function. The level of SRF mRNA expression increases ∼16% in the hearts of mice during adult aging. To model the effect of mild SRF elevation in the aging heart, transgenic mice with low levels of SRF overexpression were generated. By 6 mo of age, the transgenic mice had a 19% increase of heart-to-body weight ratio compared with nontransgenic mice. In addition, they had a 12% increase in myocyte size, a 6.7% increase in collagen deposition, and altered gene expression of a number of muscle-specific and cardiac genes. Doppler echocardiography revealed that these transgenic mice had increased left ventricular wall thickness and decreased left ventricular (LV) volumes, increased LV stiffness with 20% reduction in early diastolic LV filling (peak E), and 35% decline in peak E-to-peak A (late diastolic filling) ratio. The observed changes, especially those in the E/A ratio, are similar to those seen clinically in late life as a part of human adult myocardial aging.

scholarly journals Myozap, a Novel Intercalated Disc Protein, Activates Serum Response Factor–Dependent Signaling and Is Required to Maintain Cardiac Function In Vivo

2010 ◽  
Vol 106 (5) ◽  
pp. 880-890 ◽  
Author(s):  
Thalia S. Seeger ◽  
Derk Frank ◽  
Claudia Rohr ◽  
Rainer Will ◽  
Steffen Just ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Serum Response Factor ◽  
Response Factor ◽  
Intercalated Disc ◽  
Serum Response

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.

Functional antagonism between YY1 and the serum response factor

1992 ◽  
Vol 12 (9) ◽  
pp. 4209-4214
Author(s):  
A Gualberto ◽  
D LePage ◽  
G Pons ◽  
S L Mader ◽  
K Park ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Regulatory Element ◽  
Target Sequence ◽  
Response Factor ◽  
Basal Expression ◽  
Actin Promoter ◽  
Alpha Actin ◽  
Serum Response

The rapid, transient induction of the c-fos proto-oncogene by serum growth factors is mediated by the serum response element (SRE). The SRE shares homology with the muscle regulatory element (MRE) of the skeletal alpha-actin promoter. It is not known how these elements respond to proliferative and cell-type-specific signals, but the response appears to involve the binding of the serum response factor (SRF) and other proteins. Here, we report that YY1, a multifunctional transcription factor, binds to SRE and MRE sequences in vitro. The methylation interference footprint of YY1 overlaps with that of the SRF, and YY1 competes with the SRF for binding to these DNA elements. Overexpression of YY1 repressed serum-inducible and basal expression from the c-fos promoter and repressed basal expression from the skeletal alpha-actin promoter. YY1 also repressed expression from the individual SRE and MRE sequences upstream from a TATA element. Unlike that of YY1, SRF overexpression alone did not influence the transcriptional activity of the target sequence, but SRF overexpression could reverse YY1-mediated trans repression. These data suggest that YY1 and the SRF have antagonistic functions in vivo.

scholarly journals Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.

1993 ◽  
Vol 13 (2) ◽  
pp. 1264-1272 ◽  
Author(s):  
C K Vincent ◽  
A Gualberto ◽  
C V Patel ◽  
K Walsh
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Sequence Motif ◽  
Regulatory Sequences ◽  
Response Factor ◽  
Specific Expression ◽  
Serum Response

Regulatory sequences of the M isozyme of the creatine kinase (MCK) gene have been extensively mapped in skeletal muscle, but little is known about the sequences that control cardiac-specific expression. The promoter and enhancer sequences required for MCK gene expression were assayed by the direct injection of plasmid DNA constructs into adult rat cardiac and skeletal muscle. A 700-nucleotide fragment containing the enhancer and promoter of the rabbit MCK gene activated the expression of a downstream reporter gene in both muscle tissues. Deletion of the enhancer significantly decreased expression in skeletal muscle but had no detectable effect on expression in cardiac muscle. Further deletions revealed a CArG sequence motif at position -179 within the promoter that was essential for cardiac-specific expression. The CArG element of the MCK promoter bound to the recombinant serum response factor and YY1, transcription factors which control expression from structurally similar elements in the skeletal actin and c-fos promoters. MCK-CArG-binding activities that were similar or identical to serum response factor and YY1 were also detected in extracts from adult cardiac muscle. These data suggest that the MCK gene is controlled by different regulatory programs in adult cardiac and skeletal muscle.

scholarly journals Cardiac Tissue Enriched Factors Serum Response Factor and GATA-4 Are Mutual Coregulators

2000 ◽  
Vol 20 (20) ◽  
pp. 7550-7558 ◽  
Author(s):  
Narasimhaswamy S. Belaguli ◽  
Jorge L. Sepulveda ◽  
Vishal Nigam ◽  
Frédéric Charron ◽  
Mona Nemer ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Cardiac Tissue ◽  
Serum Response Factor ◽  
Zinc Finger Protein ◽  
Response Factor ◽  
Mads Box ◽  
Cardiovascular Tissue ◽  
Serum Response

ABSTRACT Combinatorial interaction among cardiac tissue-restricted enriched transcription factors may facilitate the expression of cardiac tissue-restricted genes. Here we show that the MADS box factor serum response factor (SRF) cooperates with the zinc finger protein GATA-4 to synergistically activate numerous myogenic and nonmyogenic serum response element (SRE)-dependent promoters in CV1 fibroblasts. In the absence of GATA binding sites, synergistic activation depends on binding of SRF to the proximal CArG box sequence in the cardiac and skeletal α-actin promoter. GATA-4's C-terminal activation domain is obligatory for synergistic coactivation with SRF, and its N-terminal domain and first zinc finger are inhibitory. SRF and GATA-4 physically associate both in vivo and in vitro through their MADS box and the second zinc finger domains as determined by protein A pullout assays and by in vivo one-hybrid transfection assays using Gal4 fusion proteins. Other cardiovascular tissue-restricted GATA factors, such as GATA-5 and GATA-6, were equivalent to GATA-4 in coactivating SRE-dependent targets. Thus, interaction between the MADS box and C4 zinc finger proteins, a novel regulatory paradigm, mediates activation of SRF-dependent gene expression.

Abstract 367: Exercising Exacerbates the Hypertrophic Response of Female Transgenic Mice Expressing Elevated Myocardial Na + /H + Exchanger Isoform 1

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fatima Mraiche ◽  
Larry Fliegel
Keyword(s):  
Transgenic Mice ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Wild Type ◽  
Cross Sectional ◽  
Hypertrophic Response ◽  
Female Mice ◽  
Gender Specific

Cardiac hypertrophy (CH) is heart growth in response to environmental demands, and a variety of hormonal, paracrine and autocrine stimuli. It is a means to reduce stress on the ventricular wall. The Na+/H+ exchanger isoform 1 (NHE1) has been implicated in the development and progression of CH. To better understand the involvement of NHE1, male and female transgenic mice that express cardiac specific active NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. NHE activity of adult ventricular cardiomyocytes and protein expression were elevated by approximately 2 and 3-fold in the N- and K-line mice vs. control. The K-line female mice assessed by echocardiography demonstrated significant global cardiac dysfunction. Left ventricular fractional cell shortening and ejection fraction were significantly decreased in the K-line mice (23.1 ± 3.8% and 45.2 ± 6.9% K-line vs. 36.5 ± 1.1% and 66.4 ± 1.5% control, respectively; p<0.05). The K-line female mice also exhibit myocardial remodeling. The heart weight to body weight ratio was significantly greater in the K-line mice (143 ± 10.0% of control; P<0.05). Cross sectional area (K-line 195.6 ± 16.4% of control; p<0.05) and interstitial fibrosis (K-line: 275.4 ± 11.6% of control; p<0.05) were also elevated. Increased expression of active NHE1 protein in male mice was also much more detrimental than expression of the wild type protein as was seen with the female transgenic mice. Therefore, the NHE1 induced hypertrophic effect was not gender dependent. However, NHE1 expression induced gender specific differences with exercise. Exercising exaggerated the HW/BW ratio in female mice expressing activated NHE1 compared to males. These results suggest that gender specific activation of NHE1 may be critical in promoting hypertrophy in females in comparison with males.

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 Delayed liver regeneration in mice lacking liver serum response factor

2007 ◽  
Vol 292 (4) ◽  
pp. G996-G1001 ◽  
Author(s):  
M. Ujue Latasa ◽  
Dominique Couton ◽  
Claude Charvet ◽  
Aurélie Lafanechère ◽  
Jacques-Emmanuel Guidotti ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Serum Response Factor ◽  
Early Response ◽  
Mutant Mice ◽  
Response Factor ◽  
Impaired Liver ◽  
Serum Response

Various immediate early genes (IEGs) upregulated during the early process of liver regeneration are transcriptional targets of the serum response factor (SRF). We show here that the expression of SRF is rapidly induced in rodent liver after partial hepatectomy. Because the inactivation of the SRF gene in mice is embryonic lethal, the in vivo role of SRF in liver regeneration after partial hepatectomy was analyzed in mutant mice conditionally deleted for SRF in the liver. We demonstrate that SRF is not an essential factor for liver ontogenesis. However, adult mutant mice show impaired liver regeneration after partial hepatectomy, associated with a blunted upregulation of various SRF target IEGs. In conclusion, our work suggests that SRF is an early response transcription factor that may contribute to the initial phases of liver regeneration through its activation of IEGs.

The single-strand DNA/RNA-binding protein, Purβ, regulates serum response factor (SRF)-mediated cardiac muscle gene expressionThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 349-359 ◽  
Author(s):  
Madhu Gupta ◽  
Vithida Sueblinvong ◽  
Mahesh P. Gupta
Keyword(s):  
Gene Expression ◽  
Cardiac Muscle ◽  
Rna Binding ◽  
Serum Response Factor ◽  
Single Strand ◽  
Specific Gene ◽  
Response Factor ◽  
Repressive Effect ◽  
Muscle Gene ◽  
Serum Response

Single-strand DNA-binding proteins, Purα and Purβ, play a role in cell growth and differentiation by modulating both transcriptional and translational controls of gene expression. We have previously characterized binding of Purα and Purβ proteins to a purine-rich negative regulatory (PNR) element of the rat cardiac α-myosin heavy chain (MHC) gene that controls cardiac muscle specificity. In this study we investigated the role of upstream sequences of the α-MHC promoter in Purβ-mediated gene repression. In the transient transfection analysis overexpression of Purβ revealed a negative regulatory effect on serum response factor (SRF)-dependent α-MHC and α-skeletal actin expression in muscle cell background. Contrary, in nonmuscle cells, Purβ showed no repressive effect. The results obtained from gel-shift assays demonstrated a sequence specific competitive binding of Purβ to the minus strand of the SRF-binding, CArG box sequences of different muscle genes, but not to the SRF-binding, SRE sequences of the c-fos gene. These element-specific associations of Purβ with muscle CArG boxes may, in part, explain why muscle gene expression is downregulated in disease states in which Purβ levels are elevated. This data also provide a mechanistic distinction between muscle CArG boxes and nonmuscle serum response element (SRE) sequences in terms of their affinity to bind to SRF and their ability to regulate cell-specific gene expression.

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