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The heparanase-syndecan-4 axis in the heart: upregulation in response to immune activation
indicates a role in cardiac inflammation
Strand ME1,2, Aronsen JM3, Skrbic B1,2,4, Gelazauskaite M1,2, Sjaastad I1,2, Christensen G1,2, Lunde IG1,2
1 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo,
Oslo, Norway.
2 Center for Heart Failure Research, University of Oslo, Oslo, Norway.
3 Bjørknes College, Oslo, Norway
4 Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Oslo, Norway.
Chronic immune activation is a central pathophysiological mechanism in the progression of heart failure,
promoting cardiac inflammation, remodeling and dysfunction. We have previously shown that the
expression and shedding of the heparan sulfate (HS) proteoglycan syndecan-4 is upregulated in response
to immune activation in failing hearts, and that the shed HS-substituted ectodomains mediate
inflammatory events. Which enzymes regulate the shedding process and modulation of shed ectodomains,
remain largely unknown. Heparanase is an endoglycosidase which cleaves HS, modulates the function of
syndecans and plays versatile roles in inflammation. The role of heparanase in heart pathology remains to
be elucidated. In this study we investigate the heparanase-syndecan-4 axis in cardiac inflammation.
Mice were subjected to pressure overload by aortic banding (AB) or lipopolysaccharide (LPS)
challenge in vivo. Left ventricular (LV) heparanase mRNA was elevated during the acute phase after AB
(AB24h; 2.8-fold; n=10) compared to sham-operated controls, which coincided with increased expression
of syndecan-4 (3.6-fold) and the proinflammatory cytokines TNFα and IL-1β (3.6- and 14.7-fold,
respectively). LPS (9h, 10mg/kg) increased LV heparanase and syndecan-4 expression (1.9- and 9.8-fold,
respectively) in wild-type (WT) mice compared to PBS-injected controls (n=8). Interestingly, LPS-induced
heparanase expression was attenuated in syndecan-4 knock-out mice and accentuated in mice with
cardiomyocyte-specific (α-MHC) overexpression of syndecan-4 compared to WT, suggesting co-regulation
of heparanase and syndecan-4 in the heart. In vitro primary cardiac cell cultures showed that heparanase
was expressed in cardiac myocytes and fibroblasts, with higher levels of both mRNA and secreted protein
in cardiomyocytes. Heparanase expression was upregulated by TNFα and IL-1β (1.5- and 2.2-fold,
respectively) in cardiomyocytes and by IL-1β and LPS (2.5- and 3.4-fold, respectively) in cardiac
fibroblasts, i.e. the same signals that induce syndecan-4 in these cells.
In conclusion, our data suggest that heparanase is induced alongside syndecan-4 by mediators of
innate immunity and may play a role in cardiac inflammation, possibly by modulating syndecan-4mediated immune responses.