title: Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice.
abstract: Laminin alpha4 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 alpha4 chain transcripts in the heart suggests an important role of this protein in cardiovascular development and function. In this study, we demonstrate that laminin alpha4 deficient mice gradually develop cardiac hypertrophy with impaired function. We show that depletion of laminin alpha4 chain did not alter the levels of dystrophin-glycoprotein complex (DGC) components or affect cell membrane integrity. No alteration in integrin beta 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 1alpha (Hif1alpha) 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 alpha4 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.
authors.affiliation: Institute of Molecular Medicine, University of California at San Diego, La Jolla 92093, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Wang
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Jason
authors.initials: J
authors.lastname: Lam
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
authors.forename: Anna
authors.initials: A
authors.lastname: Jokiel
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003326:Coronary Circulation; D016189:Dystrophin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019012:Integrin beta1 / Q000378:metabolism; D007797:Laminin / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D016189:Dystrophin; D006023:Glycoproteins; D019012:Integrin beta1; C501370:Lama4 protein, mouse; D007797:Laminin