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
Daihiko Hakuno, Naritaka Kimura, Masatoyo Yoshioka, Makio Mukai, Tokuhiro Kimura, Yasunori Okada, Ryohei Yozu, Chisa Shukunami, Yuji Hiraki, Akira Kudo, Satoshi Ogawa, Keiichi Fukuda
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Research Article

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

Abstract

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 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.

Authors

Daihiko Hakuno, Naritaka Kimura, Masatoyo Yoshioka, Makio Mukai, Tokuhiro Kimura, Yasunori Okada, Ryohei Yozu, Chisa Shukunami, Yuji Hiraki, Akira Kudo, Satoshi Ogawa, Keiichi Fukuda

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Figure 6

HF diet–induced fibrosis and MMP expression in the cardiac valve complex are reduced in Postn–/– mice.

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HF diet–induced fibrosis and MMP expression in the cardiac valve complex...
(A–C) Representative IHC sections (A), quantitative analyses of the expression areas (B), and Western blot analysis (C) of the cardiac valve complexes in WT and Postn–/– mice. (A) Horizontal sections of AV annuli and longitudinal sections of MV annuli are shown. The boxed regions in the periostin-stained sections are shown at higher magnification immediately below, and the boxed regions in the Azan-stained sections are shown as α-SMA immunofluorescence below. The areas of expression of periostin, vWF, and α-SMA and the Azan-stained areas were markedly expanded in the HF diet–fed WT mice (arrows), whereas these changes were reduced in the HF diet–fed Postn–/– mice. (B) The areas of expression in the aortic valve annulus (AVA) and mitral valve annulus (MVA) are shown as percentages relative to WT mice. (C) Murine mitral valves with annuli were excised and subjected to Western blot analysis. The expression levels of periostin, collagen I, α-SMA, MMP-2, and MMP-13 were greatly increased in the HF diet–fed WT mice and reduced in HF diet–fed Postn–/– mice. Scale bars: 100 μm; 20 μm (α-SMA immunofluorescence). *P < 0.05 versus WT; **P < 0.05 versus HF diet–fed Postn–/–.