Ski drives an acute increase in MMP-9 gene expression and release in primary cardiac myofibroblasts
| Autor: | Natalie M. Landry, Michael P. Czubryt, Morvarid S. Kavosh, Krista L. Filomeno, Sunil G. Rattan, Ian M.C. Dixon |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cardiovascular Conditions
Disorders and Treatments Male 0301 basic medicine cell migration Physiology Cardiac fibrosis cardiac fibrosis 030204 cardiovascular system & hematology MMP9 Cardiac fibroblast fibroblast activation Signalling Pathways Rats Sprague-Dawley Extracellular matrix Focal adhesion 03 medical and health sciences 0302 clinical medicine Cell Movement Proto-Oncogene Proteins Physiology (medical) Extracellular medicine Animals Myofibroblasts Cells Cultured Paxillin Original Research biology Chemistry Myocardium Heart Ski medicine.disease myofibroblast Actins Fibronectins Rats Cell biology Fibronectin 030104 developmental biology Matrix Metalloproteinase 9 biology.protein Cellular Physiology human activities Myofibroblast |
| Zdroj: | Physiological Reports |
| ISSN: | 2051-817X |
| DOI: | 10.14814/phy2.13897 |
| Popis: | Many etiologies of heart disease are characterized by expansion and remodeling of the cardiac extracellular matrix (ECM or matrix) which results in cardiac fibrosis. Cardiac fibrosis is mediated in cardiac fibroblasts by TGF‐β 1/R‐Smad2/3 signaling. Matrix component proteins are synthesized by activated resident cardiac fibroblasts known as myofibroblasts (MFB). These events are causal to heart failure with diastolic dysfunction and reduced cardiac filling. We have shown that exogenous Ski, a TGF‐β 1/Smad repressor, localizes in the cellular nucleus and deactivates cardiac myofibroblasts. This deactivation is associated with reduction of myofibroblast marker protein expression in vitro, including alpha smooth muscle actin (α‐SMA) and extracellular domain‐A (ED‐A) fibronectin. We hypothesize that Ski also acutely regulates MMP expression in cardiac MFB. While acute Ski overexpression in cardiac MFB in vitro was not associated with any change in intracellular MMP‐9 protein expression versus LacZ‐treated controls,exogenous Ski caused elevated MMP‐9 mRNA expression and increased MMP‐9 protein secretion versus controls. Zymographic analysis revealed increased MMP‐9‐specific gelatinase activity in myofibroblasts overexpressing Ski versus controls. Moreover, Ski expression was attended by reduced paxillin and focal adhesion kinase phosphorylation (FAK ‐ Tyr 397) versus controls. As myofibroblasts are hypersecretory and less motile relative to fibroblasts, Ski's reduction of paxillin and FAK expression may reflect the relative deactivation of myofibroblasts. Thus, in addition to its known antifibrotic effects, Ski overexpression elevates expression and extracellular secretion/release of MMP‐9 and thus may facilitate internal cytoskeletal remodeling as well as extracellular ECM components. Further, as acute TGF‐β 1 treatment of primary cardiac MFB is known to cause rapid translocation of Ski to the nucleus, our data support an autoregulatory role for Ski in mediating cardiac ECM accumulation. |
| Databáze: | OpenAIRE |
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