Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly

Dupuis, Loren E.; Berger, Matthew G.; Feldman, Samuel; Doucette, Lorna; Fowlkes, Vennece; Chakravarti, Shukti; Thibaudeau, Sarah; Alcala, Nicolas E.; Bradshaw, Amy D.; Kern, Christine B.

doi:10.1016/j.yjmcc.2015.04.007

Cited by 37 publications

(25 citation statements)

References 49 publications

(60 reference statements)

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“…These data represent 34 Fmod +/− ; Lum +/− X Fmod +/− ; Lum +/− litters. We previously reported a reduction in ventricular lumen area in P0 Lum −/− mice that may contribute to unexpected P0 death rates on the C57BL/6 background (Dupuis et al, ).…”

Section: Resultsmentioning

confidence: 99%

Development of myotendinous‐like junctions that anchor cardiac valves requires fibromodulin and lumican

Dupuis

Doucette

Rice

et al. 2016

Developmental Dynamics

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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. Conclusion 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.

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Section: Resultsmentioning

confidence: 99%

Development of myotendinous‐like junctions that anchor cardiac valves requires fibromodulin and lumican

Dupuis

Doucette

Rice

et al. 2016

Developmental Dynamics

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“…In comparison, the proteoglycan syndecan-4 is up-regulated 3-fold after AB in mice, yet syndecan-4 KO mice show a strong phenotype with attenuated hypertrophy, exacerbated dilatation, contractile dysfunction and pulmonary congestion post-AB [ 10 , 11 , 33 , 34 ]. LUM and FMOD compete for binding to collagen fibrils [ 35 – 37 ], and LUM-KO mice show a stronger cardiac phenotype than FMOD-KO mice with 50% perinatal death and hypertrophic growth from the neonatal stage in surviving mice [ 38 ]. Double-LUM/FMOD-KO mice show clinical features of Ehler-Danlos syndrome with joint laxity and impaired tendon integrity [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

Andenæs¹,

Lunde²,

Mohammadzadeh³

et al. 2018

PLoS ONE

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Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.

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“…LUM binds fibrillar collagens 14 , and regulates collagen fibril thickness and interfibrillar spacing, important for tissue integrity and corneal transparency 12,15 . LUM is central to development of pulmonary and hepatic fibrosis 16,17 , is abundant in fibrotic tissues including the thickened intima of human atherosclerotic coronary arteries 18 , and is present in the developing myocardium 19,20 . Transforming growth factor (TGF)β, a major pro-fibrotic growth factor, is believed to interact with LUM 21,22 .…”

Section: Introductionmentioning

confidence: 99%

The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload

Mohammadzadeh

Lunde

Andenæs

et al. 2019

Sci Rep

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Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1–14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1–10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.

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Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly

Cited by 37 publications

References 49 publications

Development of myotendinous‐like junctions that anchor cardiac valves requires fibromodulin and lumican

Development of myotendinous‐like junctions that anchor cardiac valves requires fibromodulin and lumican

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload

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