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 9

Conceptual framework for the roles of periostin and chondromodulin I in the progression of atherosclerotic and rheumatic VHD.

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Periostin induces the secretion of MMPs from VICs, ECs, and macrophages ...
The circulating CD14-positive inflammatory cells (and possibly fibrocytes) that express periostin initially infiltrate the zona atrialis/ventricularis of the cardiac valve. Thereafter, periostin secreted from these cells not only promotes angiogenesis by induction of EC migration and inhibition of EC apoptosis, but also stimulates the production of MMP-2, MMP-9, and MMP-13 by ECs, VICs, and engrafted macrophages, which advance cardiac valve degeneration. Valve degeneration in turn facilitates the infiltration of circulating periostin-expressing cells, thereby creating a vicious circle. The origin of the engrafted ECs is unknown; it is possible that periostin enhances the recruitment of circulating endothelial progenitor cells into the valves or promotes the penetration of microvessels from the annulus region or roots into the leaflets. In contrast, chondromodulin I blocks angiogenesis through inhibition of EC migration and induction of EC apoptosis, although other angioinhibitory factors are involved during the earlier stages of valve degeneration. Therefore, the equilibrium between periostin and chondromodulin I (as well as other angioinhibitory factors) defines the progression of atherosclerotic and rheumatic cardiac valve degeneration by controlling angiogenesis and MMP production.