Naiyereh Mohammadzadeh1,2, Arne Olav Melleby1,2, Sheryl Palmero1,2, Ivar Sjaastad1,2, Shukti Chakravarti3,4, Kristin V T Engebretsen5, Geir Christensen1,2, Ida G Lunde1,2,6, Theis Tønnessen7,8,9. 1. Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. 2. KG Jebsen Center for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway. 3. Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. 4. Department of Ophthalmology and Pathology, NYU Langone Health, New York, New York, USA. 5. Department of Surgery, Vestre Viken Hospital, Drammen, Norway. 6. Center for Molecular Medicine Norway, Oslo University Hospital and University of Oslo, Oslo, Norway. 7. Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway, theis.tonnessen@medisin.uio.no. 8. KG Jebsen Center for Cardiac Research and Center for Heart Failure Research, University of Oslo, Oslo, Norway, theis.tonnessen@medisin.uio.no. 9. Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway, theis.tonnessen@medisin.uio.no.
Abstract
INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR. CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.
INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR. CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.
Authors: Lise Nannan; Valérie Untereiner; Isabelle Proult; Camille Boulagnon-Rombi; Charlie Colin-Pierre; Ganesh D Sockalingum; Stéphane Brézillon Journal: Front Cell Dev Biol Date: 2020-05-12
Authors: Petra Popovics; Asha Jain; Kegan O Skalitzky; Elise Schroeder; Hannah Ruetten; Mark Cadena; Kristen S Uchtmann; Chad M Vezina; William A Ricke Journal: Int J Mol Sci Date: 2021-11-18 Impact factor: 5.923