Heart disease is a deadly syndrome affecting millions worldwide. It reflects an unmet clinical need, and the disease mechanisms are poorly understood. Cardiac
fibrosis is central to
heart disease. The four-membered family of transmembrane
proteoglycans,
syndecan-1 to -4, is believed to regulate
fibrosis. We review the current literature concerning
syndecans in cardiac
fibrosis.
Syndecan expression is up-regulated in response to pro-inflammatory stimuli in various forms of
heart disease with
fibrosis. Mice lacking
syndecan-1 and -4 show reduced activation of pro-fibrotic signaling and increased
cardiac rupture upon
infarction indicating an important role for these molecules. Whereas the short cytoplasmic tail of
syndecans regulates signaling, their extracellular part, substituted with
heparan sulfate glycosaminoglycan chains, binds a plethora of extracellular matrix (ECM) molecules involved in
fibrosis, e.g.,
collagens,
growth factors,
cytokines, and immune cell adhesion
proteins. Full-length
syndecans induce pro-fibrotic signaling, increasing the expression of
collagens, myofibroblast differentiation factors, ECM
enzymes,
growth factors, and immune
cell adhesion molecules, thereby also increasing cardiac stiffness and preventing
cardiac rupture. Upon pro-inflammatory stimuli,
syndecan ectodomains are enzymatically released from heart cells (
syndecan shedding). Shed ectodomains affect the expression of ECM molecules, promoting ECM degradation and
cardiac rupture upon
myocardial infarction. Blood levels of shed
syndecan-1 and -4 ectodomains are associated with hospitalization, mortality, and heart remodeling in patients with
heart failure. Improved understanding of
syndecans and their modifying
enzymes in cardiac
fibrosis might contribute to the development of compounds with therapeutic potential, and enzymatically shed
syndecan ectodomains might constitute a future prognostic tool for
heart diseases with
fibrosis. Graphical Abstract Graphical abstract summarizing the contents of the current review on
syndecans in cardiac
fibrosis. The heart is subjected to various forms of pathological stimuli, e.g.,
myocardial infarction,
hypertension, valvular
stenosis,
infection, or an inherited genetic mutation, triggering responses in cells resident in the heart. Here, we focus on the responses of cardiac fibroblasts directing changes in the extracellular matrix resulting in cardiac
fibrosis. A family of four transmembrane
proteoglycans,
syndecan-1 to -4, is expressed in the cell membrane of cardiac fibroblasts and is generally up-regulated in response to the above-mentioned pathological stimuli.
Syndecans carry
glycosaminoglycan chains on their extracellular domain, binding a plethora of molecules involved in
fibrosis, e.g.,
growth factors,
cytokines, immune cell adhesion
proteins, and pathogens.
Syndecans have a short cytoplasmic tail involved in pro-fibrotic signaling. The signaling and cellular processes governed by
syndecans in the heart in response to pathological stimuli regulate important aspects of extracellular matrix remodeling and
fibrosis and have mainly been studied in cardiac remodeling in response to cardiac
infarction and pressure overload. In general, adequate timing and the quantity and quality of
fibrosis are absolutely crucial for heart function and survival, determining cardiac stiffness, contractility, compliance, probability of
rupture, dilation, and diastolic and systolic function.
Syndecan-1 and -4 have mainly been studied in the heart and are discussed in this review (LV left ventricle).