Cardiomyopathy associated with microcirculation dysfunction in laminin α4 chain-deficient mice

Abstract

Laminin α4 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 α4 chain transcripts in the heart suggests an important role of this protein in cardiovascular development and function. In this study, we demonstrate that laminin α4 deficient mice gradually develop cardiac hypertrophy with impaired function. We show that depletion of laminin α4 chain did not alter the levels of dystrophin-glycoprotein complex (DGC) components or affect cell membrane integrity. No alteration in integrin β1D 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 1α(Hif1α) 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 pericapillaryECMspaces, suggesting the presence of microcirculation abnormalities in Lama4-/-mutant hearts. We thus conclude that mutation in the laminin α4 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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.