The proteoglycans lumican and fibromodulin could be potential therapeutic targets for diagnosis and treatment of cardiac fibrosis, according to Naiyereh Mohammadzadeh‘s PhD thesis.
Lack of fibromodulin mildly increases cardiac hypertrophy after aortic banding.
Thesis: Roles of the proteoglycans lumican and fibromodulin in cardiac remodeling following pressure overload
Candidate: Naiyereh Mohammadzadeh
Time: March 12, 2020 at 13:15
Place: Oslo University Hospital Ullevål, Building 6: Auditorium Røntgenavdelingen
Link to university website
(1) The proteoglycan fibromodulin is highly upregulated in explanted failing hearts, with levels three times higher than in biopsies from non-diseased hearts. Healthy mice lacking fibromodulin did not have a distinctive cardiac phenotype but fibromodulin-lacking mice developed mild left ventricular hypertrophy following aortic banding-induced pressure overload. However, lack of fibromodulin did not affect heart function or mortality.
Inflammation increases expression of fibromodulin in rat cardiomyocytes and cardiac fibroblasts. In fibroblasts, this overexpression had anti-fibrotic effects such as decreased migratory capacity and expression of molecules associated with fibrosis.
(2) Mice without lumican, another proteoglycan, have increased mortality within 14 days of aortic banding. Furthermore, lack of lumican led to reduced collagen expression, increased left ventricular dilatation, more severe contractile dysfunction, and enhanced hypertrophic remodeling.
Expression of markers of myofibroblast differentiation and proliferation, as well as molecules important for fibrosis, were increased in lumican-treated cardiac fibroblasts.
(3) On the other hand, moderate lumican deficiency attenuates fibrosis following aortic banding in mice. However, as opposed to total lack of lumican, 50 % lumican deficiency improves cardiac function and has no effect on mortality. Compared to wild type mice, the 50 % lumican mice showed less diastolic dysfunction and reduced cardiac fibrosis.
(1) Andenæs, K., Lunde, I. G., Mohammadzadeh, N., Dahl, C. P., Aronsen, J. M., Strand, M. E., Palmero, S., Sjaastad, I., Christensen, G., Engebretsen, K. V. T., & Tønnessen, T. (2018). The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling. PloS one, 13(7).
(2) Mohammadzadeh, N., Lunde, I. G., Andenæs, K., Strand, M. E., Aronsen, J. M., Skrbic, B., Marstein, H. S., Bandlien, C., Nygård, S., Gorham, J., Sjaastad, I., Chakravarti, S., Christensen, G., Engebretsen, K. V. T., & Tønnessen, T. (2019). The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload. Scientific reports, 9(1), 1-13.
(3) Mohammadzadeh, N., Melleby, A. O., Palmero, S., Sjaastad, I., Chakravarti, S., Engebretsen, K. V., Christensen, G., Lunde, I. G., & Tønnessen, T. (2020). Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload. Cardiology, 145(3), 187-199.
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