Silvia Aldi1, Linnéa Eriksson1, Malin Kronqvist1, Mariette Lengquist1, Marie Löfling1, Lasse Folkersen2, Ljubica P Matic1, Lars Maegdefessel3, Karl-Henrik Grinnemo1, Jin-Ping Li4, C Österholm5, Ulf Hedin1. 1. Department of Molecular Medicine and Surgery, Bioclinicum J8:20, Karolinska Institutet, 171 64, Solna, Sweden. 2. Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen, Denmark. 3. Department of Medicine Solna, L8:03, Karolinska Institutet, 171 76, Stockholm, Sweden; Department of Vascular Surgery, Technical University Munich, 80333, Munich, Germany. 4. Department of Medical Biochemistry and Microbiology, SciLifeLab Uppsala, The Biomedical Center, Husargatan 3, Uppsala University, 752 37, Uppsala, Sweden. 5. Department of Molecular Medicine and Surgery, Bioclinicum J8:20, Karolinska Institutet, 171 64, Solna, Sweden. Electronic address: cecilia.osterholm.corbascio@ki.se.
Abstract
BACKGROUND AND AIMS: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-β-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro. METHODS: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively. RESULTS: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation. CONCLUSIONS: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.
BACKGROUND AND AIMS: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-β-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro. METHODS: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively. RESULTS:HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation. CONCLUSIONS: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.
Authors: Ahmet Seyfeddin Gurbuz; Semi Ozturk; Suleyman Cagan Efe; Mehmet Fatih Yilmaz; Raziye Ecem Yanik; Ali Yaman; Cevat Kirma Journal: Med Princ Pract Date: 2019-09-04 Impact factor: 1.927