title: Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly.
abstract: The ability of the heart to adapt to increased stress is dependent on the modification of its extracellular matrix (ECM) architecture that is established during postnatal development as cardiomyocytes differentiate, a process that is poorly understood. We hypothesized that the small leucine-rich proteoglycan (SLRP) lumican (LUM), which binds collagen and facilitates collagen assembly in other tissues, may play a critical role in establishing the postnatal murine myocardial ECM. Although previous studies suggest that LUM deficient mice (lum(-/-)) exhibit skin anomalies consistent with Ehlers-Danlos syndrome, lum(-/-) hearts have not been evaluated. These studies show that LUM was immunolocalized to non-cardiomyocytes of the cardiac ventricles and its expression increased throughout development. Lumican deficiency resulted in significant (50%) perinatal death and further examination of the lum(-/-) neonatal hearts revealed an increase in myocardial tissue without a significant increase in cell proliferation. However cardiomyocytes from surviving postnatal day 0 (P0), 1 month (1 mo) and adult (4 mo) lum(-/-) hearts were significantly larger than their wild type (WT) littermates. Immunohistochemistry revealed that the increased cardiomyocyte size in the lum(-/-) hearts correlated with alteration of the cardiomyocyte pericellular ECM components collagenα1(I) and the class I SLRP decorin (DCN). Western blot analysis demonstrated that the ratio of glycosaminoglycan (GAG) decorated DCN to core DCN was reduced in P0 and 1 mo lum(-/-) hearts. There was also a reduction in the β and γ forms of collagenα1(I) in lum(-/-) hearts. While the total insoluble collagen content was significantly reduced, the fibril size was increased in lum(-/-) hearts, indicating that LUM may play a role in collagen fiber stability and lateral fibril assembly. These results suggest that LUM controls cardiomyocyte growth by regulating the pericellular ECM and also indicates that LUM may coordinate multiple factors of collagen assembly in the murine heart. Further investigation into the role of LUM may yield novel therapeutic targets and/or biomarkers for patients with cardiovascular disease.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Loren E
authors.initials: LE
authors.lastname: Dupuis
authors.affiliation: Honors College, College of Charleston, Charleston, SC 29401, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Berger
authors.affiliation: Honors College, College of Charleston, Charleston, SC 29401, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Feldman
authors.affiliation: Honors College, College of Charleston, Charleston, SC 29401, United States.
authors.forename: Lorna
authors.initials: L
authors.lastname: Doucette
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Vennece
authors.initials: V
authors.lastname: Fowlkes
authors.affiliation: Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.
authors.forename: Shukti
authors.initials: S
authors.lastname: Chakravarti
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Thibaudeau
authors.affiliation: Honors College, College of Charleston, Charleston, SC 29401, United States.
authors.forename: Nicolas E
authors.initials: NE
authors.lastname: Alcala
authors.affiliation: Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Bradshaw
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: kernc@musc.edu.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Kern
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D048429:Cell Size; D011508:Chondroitin Sulfate Proteoglycans / Q000172:deficiency* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism* / Q000648:ultrastructure; D058575:Decorin / Q000378:metabolism; D047108:Embryonic Development; D005333:Fetus / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006984:Hypertrophy; D007632:Keratan Sulfate / Q000172:deficiency* / Q000378:metabolism; D000071234:Lumican; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008970:Molecular Weight; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D020033:Protein Isoforms / Q000378:metabolism; D012995:Solubility
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D058575:Decorin; D006025:Glycosaminoglycans; C000604307:Lum protein, mouse; D000071234:Lumican; D020033:Protein Isoforms; D003094:Collagen; D007632:Keratan Sulfate
keywords: Cardiomyocyte; Collagen; Decorin; Lumican; Myocardium; SLRP