Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents

Daihiko Hakuno, Naritaka Kimura, Masatoyo Yoshioka, Makio Mukai, Tokuhiro Kimura, Yasunori Okada, Ryohei Yozu, Chisa Shukunami, Yuji Hiraki, Akira Kudo, Satoshi Ogawa, Keiichi Fukuda
2011 Journal of Clinical Investigation  
Valvular heart disease (VHD) is the term given to any disease process involving one or more of the heart valves. The condition can be congenital or acquired, for example as a result of atherosclerosis or rheumatic fever. Despite its clinical importance, the molecular mechanisms underlying VHD remain unknown. We investigated the pathophysiologic role and molecular mechanism of periostin, a protein that plays critical roles in cardiac valve development, in degenerative VHD. Unexpectedly, we found
more » ... that periostin levels were drastically increased in infiltrated inflammatory cells and myofibroblasts in areas of angiogenesis in human atherosclerotic and rheumatic VHD, whereas periostin was localized to the subendothelial layer in normal valves. The expression patterns of periostin and chondromodulin I, an angioinhibitory factor that maintains cardiac valvular function, were mutually exclusive. In WT mice, a high-fat diet markedly increased aortic valve thickening, annular fibrosis, and MMP-2 and MMP-13 expression levels, concomitant with increased periostin expression; these changes were attenuated in periostin-knockout mice. In vitro and ex vivo studies revealed that periostin promoted tube formation and mobilization of ECs. Furthermore, periostin prominently increased MMP secretion from cultured valvular interstitial cells, ECs, and macrophages in a cell type-specific manner. These findings indicate that, in contrast to chondromodulin I, periostin plays an essential role in the progression of cardiac valve complex degeneration by inducing angiogenesis and MMP production. Periostin induces the secretion of MMPs from VICs, ECs, and macrophages in vitro. (A) Light microscopy, immunofluorescence staining, and Western blot analysis of cultured rat VICs. The VICs were fibroblast-like in appearance and expressed chondromodulin I, but did not express acetylated LDL. The ECs in the inset and the rat eye in the Western blot served as positive controls. Scale bars: 100 μm. (B) Expression and secretion of collagen I, α-SMA, MMP-2, and MMP-13 by VICs following periostin stimulation. Conditioned media and cell lysates were obtained from VICs with or without periostin stimulation and subjected to Western blot analysis. Periostin prominently stimulated secretion of MMP-2 and MMP-13 by VICs, whereas collagen I production and α-SMA expression were unchanged. Densitometric quantitative analysis of MMP levels in the conditioned media from the VIC cultures is also shown. (C) RT-PCR analysis of MMP expression in VICs after periostin stimulation. Periostin increased the transcription of Mmp13, but not that of Mmp2 or Mmp9. Cartilage served as a positive control. Also shown is Mmp2 mRNA expression in VICs after stimulation with or without periostin for 5 days. (D and E) Expression and secretion of MMPs by human coronary artery ECs (D) and cultured mouse BM-derived macrophages (E) following periostin stimulation. Densitometric quantitative analyses of MMP levels in the conditioned media from cultures of ECs and macrophages is also shown. Periostin significantly induced secretion of MMP-2 and MMP-9 from ECs and macrophages, respectively. *P < 0.05.
doi:10.1172/jci45853 fatcat:nrzogd6px5a2zndcu5nflddvzy