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Differential Regulation of CCN1 During Valve Remodeling in TGFβ isoform Activation, Collagen production through Integrin Signaling.
Author(s) -
Ghatak Shibnath,
Misra Suniti,
Moreno Rodriguez Ricardo,
Sugi Yukiko,
Hascall Vincent,
Markwald Roger
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.553.5
Subject(s) - microbiology and biotechnology , cyr61 , kinase , integrin , extracellular matrix , mapk/erk pathway , transforming growth factor , signal transduction , chemistry , extracellular , biology , growth factor , cell , biochemistry , ctgf , receptor
The failure of CCN1 null mice to form an atrioventricular (AV) septum has provided us with a unique opportunity to test mechanistic hypotheses to explain the role of CCN1 in valvular cushion development. Methods and Results We tested the hypothesis that CCN1 is a secreted signaling molecule that activates integrin dependent intracellular kinases generally associated with such phenomena as cell adhesion, DNA synthesis, and/or secretion of extracellular matrix, including hyaluronan (HA). Next, we found that, CCN1 does not induce cell proliferation on its own but enhances DNA synthesis induced by other mitogens, including bFGF and PDGF, and also induced by low MW HA (LMWHA; 150 kD, and 500 kD). Further, we found that CCN1 regulates HA synthase2 and hence stimulates synthesis of HA . Further, CCN1 binding to β‐3 integrin activated p‐Erk and p‐Fak kinases that were required to increase activated MMP‐1 (collagenase), indicating that CCN1 and HA induced by CCN1 combine to activate MMP‐1 through Erk pathway. In contrast to LMWHA, CCN1 with native HA (HMWHA) induced TGFβ3, not TGFβ1, and collagen III, not collagen I, expression. Conclusion In summary,this study provides direct evidence that endocardially secreted CCN1 can stimulate cushion development and maturation into valve leaflets and that effect of CCN1 can be influenced by HA Research Support :2R01 HL033756‐24A2, 1R03 CA167722‐01.