Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents
Daihiko Hakuno, … , Satoshi Ogawa, Keiichi Fukuda
Daihiko Hakuno, … , Satoshi Ogawa, Keiichi Fukuda
Published June 14, 2010
Citation Information: J Clin Invest. 2010;120(7):2292-2306. https://doi.org/10.1172/JCI40973.
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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 5

HF diet–induced thickening of the aortic valves and annuli is attenuated in Postn–/– mice.

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HF diet–induced thickening of the aortic valves and annuli is attenuated...
(A) Generation of Postn–/– mice. Schema of the strategy used for targeting the first exon of the murine Postn gene. Genotyping of mouse offspring was performed by PCR of tail-DNA samples. The primer pair used is indicated by arrows in the schema. Also shown is Western blot analysis of the periostea in the WT and Postn–/– (KO) mice. (B) Appearance of mice fed normal diet or HF diet for 4 months. The HF diet caused similar levels of obesity and hypercholesterolemia in both WT and Postn–/– mice. (C and D) Representative images (C) and quantitative analyses of the aortic valve thicknesses and echogenic areas of the annuli (D), as assessed by 45-MHz echocardiography. In C, images were taken at the diastolic phase using the 2D mode, and at the level of the aortic valve using the M-mode of the left parasternal long axis view. The echogenic areas of the aortic and mitral valve annuli greatly increased in the HF diet–fed WT mice (double arrows) compared with those in the WT mice (arrows). These changes were reduced in the HF diet–fed Postn–/– mice (arrowheads). Furthermore, the HF diet–induced thickening of the aortic valves was significantly attenuated in the HF diet–fed Postn–/– mice (triple arrowheads). Original magnification, ×10; ×40 (higher magnification). *P < 0.05 versus WT; **P < 0.05 versus HF diet–fed Postn–/–.