Syndecans in heart fibrosis

Abstract

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 matr...

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

“…Although there is no direct proof that mechanical forces alone can induce the release of ECM-derived DAMPs, it is plausible that high mechanical load will cause some degree of ECM damage with the consequence of DAMP release. SLRPs, syndecans, glypicans and hyaluronic synthase (HAS) 1 and 2 are upregulated in the pressure overloaded heart [104,105,109,110,111,112] and could represent such DAMPs in the mechanically stressed heart. …”

“…They are attached to the ECM as well as the cytoskeleton thereby forming a physical link from the exterior to the interior of the cell. Of these transmembrane adhesion proteins, integrins are the best understood when it comes to mechanotransduction [114] but also other proteins such as transmembrane proteoglycans [109] can transmit mechanical signals across the membrane (Figure 3). Since mechanotransduction can occur in both directions, cell surface signaling through adhesion receptors is often referred to as inside-out and outside-in signaling [115,116].…”

“…In aortic stenosis patients and mouse models of myocardial infarction and pressure overload, a role for full-length syndecan-4 in stress-induced fibrosis has been shown [109]. Syndecan-4 is expressed in cardiac fibroblasts as well as myocytes and affect remodeling related to both cell types in the pressure-overloaded hearts of mice and men [111].…”

“…Functionally, shedding of syndecan-4 in the heart represents an important aspect of syndecan-4 biology [109,163]. Cardiac fibroblasts in culture exposed to increased levels of shed syndecan-4 respond with altered expression of ECM genes [106], favoring ECM degradation.…”

Effect of QSKL on MAPK and RhoA Pathways in a Rat Model of Heart Failure

“…Heart failure (HF) is one of the leading causes of death worldwide and myocardial fibrosis is a critical pathological process in the development of HF [1]. Fibrosis is a scarring process that is characterized by the accumulation of fibroblasts and abnormal deposition of extracellular matrix (ECM) proteins, which lead to remodeled cardiac structures and impaired cardiac functions [2].…”