Abstract 12767: Syndecan-4 Regulates Myocardial Stiffness by Inducing Myofibroblast Differentiation, Extracellular Matrix Production and Collagen Cross-linking in Response to Pressure Overload
Pressure overload of the heart leads to remodeling of the left ventricle (LV) involving excessive production of extracellular matrix (ECM) by activated cardiac fibroblasts that differentiate into contractile myofibroblasts. This compromises heart function by increasing myocardial stiffness. The molecular mechanisms underlying stress-induced myofibroblast differentiation and the role of this process in regulating cardiac stiffness are poorly defined. We recently identified the focal adhesion proteoglycan syndecan-4 as important for myofibroblast differentiation in response to mechanical stress. Here we investigate the effect of syndecan-4 deletion on the mechanical properties of the LV following pressure overload.
Passive tension was reduced in muscle fiber bundles from LVs of syndecan-4-/- (syn4-/-) mice compared to wild-type (WT) mice and increased in both genotypes following aortic banding, albeit to a lower degree in syn4-/- mice. Salt extraction of myosin and actin filaments was performed to eliminate the effect of titin, a cardiac protein which is central in determining passive tension. This had no effect on passive tension following aortic banding, indicating that the reduced passive tension in syn4-/- mice was due to alterations in the extracellular matrix and not changes in titin. Consistent with this, quantification of ECM, fibroblasts and blood vessels by electron microscopy, revealed increased number of fibroblasts in LVs of WT mice and reduced amount of ECM in syn4-/- mice. Furthermore, total collagen content was only significantly increased in LVs of WT mice. Initial effects of 24 hrs aortic banding included a ~50-fold increase in mRNA levels of the collagen cross-linking enzyme lysyl oxidase (LOX) in WT LVs, whereas this response was significantly blunted (~25-fold increase) in syn4-/- mice. Supporting these findings, LOX activity was reduced in LVs of syn4-/- mice, indicating impaired cross-linking of collagen in syn4-/- mice.
In conclusion, we demonstrate reduced passive tension in LV tissue of syn4-/- mice likely due to inhibited differentiation of fibroblasts into myofibroblasts, reduced extracellular matrix production and attenuated collagen cross-linking.
- © 2013 by American Heart Association, Inc.