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J. Biol. Chem., Vol. 281, Issue 1, 213-220, January 6, 2006

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Cardiomyopathy Associated with Microcirculation Dysfunction in Laminin 4 Chain-deficient Mice^*

Jianming Wang, Masahiko Hoshijima, Jason Lam, Zhongjun Zhou¶, Anna Jokiel||, Nancy D. Dalton, Kjell Hultenby**, Pilar Ruiz-Lozano, John Ross, Jr., Karl Tryggvason, and Kenneth R. Chien1

From the Institute of Molecular Medicine, the Department of Medicine, and the ^||Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, the ^¶Department of Biochemistry, Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong, China, the ^**Department of Pathology, Karolinska Institutet, Huddinge University Hospital, Huddinge, SE-14183 Sweden, the Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SE-17177 Sweden, and The Burnham Institute, La Jolla, California 92037

Laminin 4 chain is a component of extracellular matrix (ECM) laminin-8 and -9 and serves dual roles as a structure protein and as a signaling molecule. The abundance of laminin 4 chain transcripts in the heart suggests an important role of this protein in cardiovascular development and function. In this study, we demonstrate that laminin 4 deficient mice gradually develop cardiac hypertrophy with impaired function. We show that depletion of laminin 4 chain did not alter the levels of dystrophin-glycoprotein complex (DGC) components or affect cell membrane integrity. No alteration in integrin 1D protein was observed in terms of expression level or distribution pattern, indicating that the postnatal development of cardiac hypertrophy and cardiomyopathy in these mice is unlikely associated with the stability of sarcolemmal DGC and integrin complexes. Moreover, cardiomyocytes isolated from Lama4–/– mutant hearts maintained their contractility in vitro. In contrast, elevated levels of hypoxia-inducible factor 1 (Hif1) and vascular endothelial growth factor A (Vegfa) transcripts, along with multiple foci of cardiomyocyte degeneration and fibrosis suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillary ECM spaces, suggesting the presence of microcirculation abnormalities in Lama4–/– mutant hearts. We thus conclude that mutation in the laminin 4 chain leads to abnormal cardiovascular ECM structure that cause insufficient oxygen supply to the heart and the subsequent ischemic cardiac phenotype observed. Our study links the genetic deficiency of an ECM protein to cardiomyopathy and implies a novel pathway of idiopathic cardiomyopathy in human.

Received for publication, May 9, 2005 , and in revised form, September 26, 2005.

^* This work was supported in part by National Institutes of Health Grant HL077181-01 A1 (to K. R. C.), the Swedish Research Council (to K. T.), the Novo Nordisk Foundation (to K. T.), a Karolinska postdoctoral fellowship (to J. W.), and by an American Heart Association postdoctoral fellowship (to J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1, 2, 3.

¹ To whom correspondence should be addressed. E-mail: kchien{at}partners.org.

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