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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cardiovasc+Res 2017 ; 113 (13): 1639-52 Nephropedia Template TP
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Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKC? signalling and cross-talk with TGF? #MMPMID29016732
Borland SJ; Morris TG; Borland SC; Morgan MR; Francis SE; Merry CL; Canfield AE
Cardiovasc Res 2017[Nov]; 113 (13): 1639-52 PMID29016732show ga
Aims: Vascular calcification is a major cause of morbidity and mortality. Fibroblast growth factor-2 (FGF-2) plays an instructive role in osteogenesis and bone development, but its role in vascular calcification was unknown. Therefore, we investigated the involvement of FGF-2 in vascular calcification and determined the mechanism by which it regulates this process. Methods and results: We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced to deposit a mineralized matrix by incubation with ?-glycerophosphate. FGF-2 is also localized to sites of calcification within human atherosclerotic plaques. The expression of syndecan-4, a heparan sulfate proteoglycan which regulates FGF-2 signalling, is also increased in mineralizing VSMCs and co-localizes with FGF-2 in human calcified atherosclerotic plaques. Exogenous FGF-2 inhibits VSMC mineralization, and this inhibition is reduced when syndecan-4 expression is knocked-down using siRNA. Biochemical inhibition of FGFR signalling using a pan FGFR inhibitor (BGJ398) or knocking-down syndecan-4 expression in VSMCs using siRNA increases VSMC mineralization. These increases are prevented by inhibiting transforming growth factor-? (TGF?) signalling with SB431542, suggesting cross-talk between FGF-2 and TGF? signalling is crucial for the regulation of VSMC mineralization. Syndecan-4 can also regulate FGF-2 signalling directly via protein kinase C? (PKC?) activation. Biochemical inhibition of PKC? activity using Gö6976, or siRNA-mediated suppression of PKC? expression increases VSMC mineralization; this increase is also prevented with SB431542. Finally, the ability of FGF-2 to inhibit VSMC mineralization is reduced when PKC? expression is knocked-down. Conclusion: This is the first demonstration that syndecan-4 promotes FGF-2 signalling, and in turn, suppresses VSMC mineralization by down-regulating TGF? signalling. Our discoveries that FGF-2 and syndecan-4 expression is increased in mineralizing VSMCs and that PKC? regulates FGF-2 and TGF? signalling in VSMCs suggests that the syndecan-4/FGF-2/TGF? signalling axis could represent a new therapeutic target for vascular calcification.
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Cardiovasc+Res 2017 ; 113 (13): 1639-52
