Loren E Dupuis1, Lorna Doucette1, A Kittrell Rice1, Ashton E Lancaster1, Matthew G Berger1, Shukti Chakravarti2, Christine B Kern3. 1. Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina. 2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 3. Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina. kernc@musc.edu.
Abstract
BACKGROUND: There are many patients that exhibit connective tissue related cardiac malformations but do not have mutations in collagen genes. The Small Leucine Rich Proteoglycans (SLRP) fibromodulin (FMOD) and lumican (LUM) bind collagen and regulate fibril assembly in other biological contexts. RESULTS: FMOD deficient mice and double deficient FMOD; LUM mice exhibited anomalies in regions where cardiac valve tissue interdigitates with adjacent muscle for support. Ectopic connective and/or myocardial tissue(s) was associated with the more severe cardiac valve anomalies in FMOD; LUM deficient mice. At postnatal day 0 (P0) there was an increase in the mesenchymal cell number in the regions where valve cusps anchor in FMOD; LUM deficient mice compared to WT. The cardiac valve anomalies correlated with the highest levels of FMOD expression in the heart and also where myotendinous junctions (MTJ) components biglycan, collagen type I alpha 1, and collagen type VI, are also localized. CONCLUSIONS: The postnatal assembly of the collagen-rich ECM in regions where cardiac valves anchor, that we have designated 'myotendinous-like junctions' (MTLJ) requires the SLRPs FMOD and LUM. Moreover, FMOD and LUM may facilitate mesenchymal cell differentiation in late stages of cardiac valve development. Developmental Dynamics 245:1029-1042, 2016.
BACKGROUND: There are many patients that exhibit connective tissue related cardiac malformations but do not have mutations in collagen genes. The Small Leucine Rich Proteoglycans (SLRP) fibromodulin (FMOD) and lumican (LUM) bind collagen and regulate fibril assembly in other biological contexts. RESULTS:FMOD deficient mice and double deficient FMOD; LUMmice exhibited anomalies in regions where cardiac valve tissue interdigitates with adjacent muscle for support. Ectopic connective and/or myocardial tissue(s) was associated with the more severe cardiac valve anomalies in FMOD; LUM deficient mice. At postnatal day 0 (P0) there was an increase in the mesenchymal cell number in the regions where valve cusps anchor in FMOD; LUM deficient mice compared to WT. The cardiac valve anomalies correlated with the highest levels of FMOD expression in the heart and also where myotendinous junctions (MTJ) components biglycan, collagen type I alpha 1, and collagen type VI, are also localized. CONCLUSIONS: The postnatal assembly of the collagen-rich ECM in regions where cardiac valves anchor, that we have designated 'myotendinous-like junctions' (MTLJ) requires the SLRPs FMOD and LUM. Moreover, FMOD and LUM may facilitate mesenchymal cell differentiation in late stages of cardiac valve development. Developmental Dynamics 245:1029-1042, 2016.
Authors: Marja Majava; Paul N Bishop; Pasi Hägg; Paul G Scott; Aine Rice; Chris Inglehearn; Christopher J Hammond; Tim D Spector; Leena Ala-Kokko; Minna Männikkö Journal: Hum Mutat Date: 2007-04 Impact factor: 4.878
Authors: Guiyun Zhang; Shoujun Chen; Silvia Goldoni; Bennett W Calder; Holly C Simpson; Rick T Owens; David J McQuillan; Marian F Young; Renato V Iozzo; David E Birk Journal: J Biol Chem Date: 2009-01-09 Impact factor: 5.157
Authors: N S Pellegata; J L Dieguez-Lucena; T Joensuu; S Lau; K T Montgomery; R Krahe; T Kivelä; R Kucherlapati; H Forsius; A de la Chapelle Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Kristin V T Engebretsen; Ida G Lunde; Mari E Strand; Anne Waehre; Ivar Sjaastad; Henriette S Marstein; Biljana Skrbic; Christen P Dahl; Erik T Askevold; Geir Christensen; Johannes L Bjørnstad; Theis Tønnessen Journal: FEBS J Date: 2013-04-02 Impact factor: 5.542
Authors: Tugba Can; Laura Faas; David A Ashford; Adam Dowle; Jerry Thomas; Peter O'Toole; Gonzalo Blanco Journal: Proteome Sci Date: 2014-05-07 Impact factor: 2.480
Authors: Naiyereh Mohammadzadeh; Ida G Lunde; Kine Andenæs; Mari E Strand; Jan Magnus Aronsen; Biljana Skrbic; Henriette S Marstein; Caroline Bandlien; Ståle Nygård; Joshua Gorham; Ivar Sjaastad; Shukti Chakravarti; Geir Christensen; Kristin V T Engebretsen; Theis Tønnessen Journal: Sci Rep Date: 2019-06-24 Impact factor: 4.379
Authors: Dahai Xiao; Tangzhao Liang; Ze Zhuang; Ronghan He; Jianhua Ren; Shihai Jiang; Lei Zhu; Kun Wang; Dehai Shi Journal: FEBS Open Bio Date: 2020-10-25 Impact factor: 2.792