Abstract
A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.
Highlights
Cardiac fibroblasts (CFs) play a crucial role in the physiological maintenance of extracellular matrix (ECM) and in many pathologies of the heart including myocardial infarction, hypertension, and cardiomyopathy
One model of volume overload (VO) heart failure (HF), there is a decrease in left ventricle (LV) interstitial collagen content, downregulation of several profibrotic factors (i.e., connective tissue growth factor (CTGF) and genes related to TGF-β signaling pathway) and extracellular matrix genes, as well as an increase in matrix metalloproteinases [13]
We present data that suggest the importance of substrate stiffness on CF phenotype with increased stiffness promoting cytoskeletal protein production, increased nuclear translocation of transcriptional activators (YAP and MRTFA), and decreased expression of transcriptional repressors (PPAR-γ) in normal CFs
Summary
Cardiac fibroblasts (CFs) play a crucial role in the physiological maintenance of extracellular matrix (ECM) and in many pathologies of the heart including myocardial infarction, hypertension, and cardiomyopathy. Most studies looking at CFs are framed in the context of the fibroblast-to-myofibroblast transition and emphasize strategies to make CFs less fibrotic In these studies, quiescent fibroblasts become proto-myofibroblasts with increased cytoskeletal tension and are activated into myofibroblasts with the addition of TGF-β [5,6]. One model of VO HF, there is a decrease in LV interstitial collagen content, downregulation of several profibrotic factors (i.e., CTGF and genes related to TGF-β signaling pathway) and extracellular matrix genes, as well as an increase in matrix metalloproteinases [13]. CFs from VO hearts exhibited reduced secretion of connective tissue growth factor (CTGF), reduced levels of αSMA, and increased MMP-13 expression relative to CF isolated from control hearts [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
