Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents.
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.
Hakuno
Daihiko
D
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo 160-8582, Japan.
Kimura
Naritaka
N
Yoshioka
Masatoyo
M
Mukai
Makio
M
Kimura
Tokuhiro
T
Okada
Yasunori
Y
Yozu
Ryohei
R
Shukunami
Chisa
C
Hiraki
Yuji
Y
Kudo
Akira
A
Ogawa
Satoshi
S
Fukuda
Keiichi
K
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000503:physiopathology*; D006350:Heart Valve Prosthesis; D006351:Heart Valves / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012214:Rheumatic Heart Disease / Q000378:metabolism; D012377:Rodentia / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020782:Matrix Metalloproteinases