This Article Full Text Full Text (PDF) All Versions of this Article: 112/19/2930    most recent CIRCULATIONAHA.105.533778v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parlakian, A. Articles by Li, Z. Search for Related Content PubMed PubMed Citation Articles by Parlakian, A. Articles by Li, Z. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Cardiomyopathy Related Collections Contractile function Other heart failure Animal models of human disease Physiological and pathological control of gene expression Myocardial cardiomyopathy disease Related Article

(Circulation. 2005;112:2930-2939.)
© 2005 American Heart Association, Inc.

Heart Failure

Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the SRF Gene in Adult Heart

Ara Parlakian, PhD^*; Claude Charvet, MS^*; Brigitte Escoubet, MD, PhD; Mathias Mericskay, PhD; Jeffery D. Molkentin, PhD; Guillaume Gary-Bobo, MS; Leon J. De Windt, PhD; Marie-Aline Ludosky, MS; Denise Paulin, PhD; Dominique Daegelen, PhD; David Tuil, PhD; Zhenlin Li, PhD

From the Université Paris 7, Molecular Biology of Differentiation, EA300, Paris, France (A.P., D.P.); Institut Cochin, Université René Descartes-Paris 5, INSERM U567, UMR CNRS 8104, Paris, France (C.C., D.D., D.T.); Faculté de Médecine Xavier-Bichat, Université Paris 7, Assistance Publique-Hôpitaux de Paris, INSERM U426, CEFI IFR02, Paris, France (B.E.); Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio (J.D.M.); Hubrecht Laboratory and Interuniversity Cardiology Institute, Utrecht, Netherlands (L.J. De W.); Institut Jacques Monod, UMR 7592, Paris, France (M.L.); and Université Pierre et Marie Curie, Physiology and Physiopathology, UMR 7079, Paris, France (M.M., G.G.-B., Z.L.).

Correspondence to Zhenlin Li, PhD, UMR CNRS 7079, Physiology and Physiopathology, BP256, Université Pierre et Marie Curie, 7 Quai St-Bernard, 75005 Paris, France. E-mail zhenli{at}ccr.jussieu.fr

Received January 5, 2005; revision received July 4, 2005; accepted July 18, 2005.

Background— Serum response factor (SRF) is a cardiac transcription factor involved in cell growth and differentiation. We have shown, using the Cre/loxP system, that cardiac-specific disruption of SRF gene in the embryonic heart results in lethal cardiac defects. The role of SRF in adult heart is unknown.

Methods and Results— We disrupted SRF in the adult heart using a heart-specific tamoxifen-inducible Cre recombinase. This disruption led to impaired left ventricular function with reduced contractility, subsequently progressing to dilated cardiomyopathy, as demonstrated by serial echocardiography, including tissue Doppler imaging. The cytoarchitecture of cardiomyocytes was altered in the intercalated disks. All mutant mice died from heart failure 10 weeks after treatment. These functional and structural defects were preceded by early alterations in the cardiac gene expression program: major decreases in mRNA levels for cardiac -actin, muscle creatine kinase, and calcium-handling genes.

Conclusions— SRF is crucial for adult cardiac function and integrity. We suggest that the rapid progression to heart failure in SRF mutant mice results primarily from decreased expression of proteins involved in force generation and transmission, low levels of polymerized actin, and changes in cytoarchitecture, without hypertrophic compensation. These cardiac-specific SRF-deficient mice have the morphological and clinical features of acquired dilated cardiomyopathy in humans and may therefore be used as an inducible model of this disorder.

---

 

CLINICAL PERSPECTIVE

Related Article:

Heart Failure Research Continues to Reveal the Flaws in Nature’s Unintelligent Design

Douglas B. Sawyer
Circulation 2005 112: 2891-2893. [Extract] [Full Text]

This article has been cited by other articles:

				G. Gary-Bobo, A. Parlakian, B. Escoubet, C. A. Franco, S. Clement, P. Bruneval, D. Tuil, D. Daegelen, D. Paulin, Z. Li, et al. Mosaic inactivation of the serum response factor gene in the myocardium induces focal lesions and heart failure Eur J Heart Fail, July 1, 2008; 10(7): 635 - 645. [Abstract] [Full Text] [PDF]

				L. Vinet, P. Rouet-Benzineb, X. Marniquet, N. Pellegrin, L. Mangin, L. Louedec, J.-L. Samuel, and J.-J. Mercadier Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H352 - H360. [Abstract] [Full Text] [PDF]

				T. Ogata, T. Ueyama, K. Isodono, M. Tagawa, N. Takehara, T. Kawashima, K. Harada, T. Takahashi, T. Shioi, H. Matsubara, et al. MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance Mol. Cell. Biol., May 15, 2008; 28(10): 3424 - 3436. [Abstract] [Full Text] [PDF]

				M. I. Kontaridis, W. Yang, K. K. Bence, D. Cullen, B. Wang, N. Bodyak, Q. Ke, A. Hinek, P. M. Kang, R. Liao, et al. Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways Circulation, March 18, 2008; 117(11): 1423 - 1435. [Abstract] [Full Text] [PDF]

				N. Randrianarison, B. Escoubet, C. Ferreira, A. Fontayne, N. Fowler-Jaeger, C. Clerici, E. Hummler, B. C. Rossier, and C. Planes beta-Liddle mutation of the epithelial sodium channel increases alveolar fluid clearance and reduces the severity of hydrostatic pulmonary oedema in mice J. Physiol., July 15, 2007; 582(2): 777 - 788. [Abstract] [Full Text] [PDF]

				M. U. Latasa, D. Couton, C. Charvet, A. Lafanechere, J.-E. Guidotti, Z. Li, D. Tuil, D. Daegelen, C. Mitchell, and H. Gilgenkrantz Delayed liver regeneration in mice lacking liver serum response factor Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G996 - G1001. [Abstract] [Full Text] [PDF]

				M. S. Parmacek Myocardin-Related Transcription Factors: Critical Coactivators Regulating Cardiovascular Development and Adaptation Circ. Res., March 16, 2007; 100(5): 633 - 644. [Abstract] [Full Text] [PDF]

				E. van Rooij, L. B. Sutherland, N. Liu, A. H. Williams, J. McAnally, R. D. Gerard, J. A. Richardson, and E. N. Olson A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure PNAS, November 28, 2006; 103(48): 18255 - 18260. [Abstract] [Full Text] [PDF]

				C. Charvet, C. Houbron, A. Parlakian, J. Giordani, C. Lahoute, A. Bertrand, A. Sotiropoulos, L. Renou, A. Schmitt, J. Melki, et al. New Role for Serum Response Factor in Postnatal Skeletal Muscle Growth and Regeneration via the Interleukin 4 and Insulin-Like Growth Factor 1 Pathways. Mol. Cell. Biol., September 1, 2006; 26(17): 6664 - 6674. [Abstract] [Full Text] [PDF]

				D. B. Sawyer Heart Failure Research Continues to Reveal the Flaws in Nature's Unintelligent Design Circulation, November 8, 2005; 112(19): 2891 - 2893. [Full Text] [PDF]