期刊
CARDIOVASCULAR PATHOLOGY
卷 16, 期 5, 页码 268-276出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.carpath.2007.03.006
关键词
aortic valve interstitial cells; degenerative valve disease; TGF-beta 1; heart valve remodeling; myofibroblasts
资金
- NHLBI NIH HHS [R01 HL070969, HL68816, R01 HL089750-01, R01 HL089750, R01 HL068816, R01 HL068816-04A2] Funding Source: Medline
Background: Phenotypically, aortic valve interstitial cells are dynamic myofibroblasts, appearing contractile and activated in times of development, disease, and remodeling. The precise mechanism of phenotypic modulation is unclear, but it is speculated that both biomechanical and biochemical factors are influential. Therefore, we hypothesized that isolated and combined treatments of cyclic tension and transforming growth factor-beta 1 would alter the phenotype and subsequent collagen biosynthesis of aortic valve interstitial cells in situ. Methods and results: Porcine aortic valve leaflets received 7- and 14-day treatments of 15% cyclic stretch (Tension); 0.5 ng/ml transforming growth factor-beta 1 (TGF); 15% cyclic stretch and 0.5 ng/ml transforming growth factor-beta 1 (Tension+TGF), or neither mechanical nor cytokine stimuli (Null). Tissues were homogenized and assayed for aortic valve interstitial cell phenotype (smooth muscle a-actin) and collagen biosynthesis (via heat shock protein 47, which was further verified with type I collagen C-terminal propeptide). At both 7 and 14 days, smooth muscle alpha-actin, beat shock protein 47, and type I collagen C-terminal propeptide quantities were significantly greater (P<.001) in the Tension+TGF group than in all other groups. Additionally, Tension alone appeared to maintain smooth muscle a-actin and heat shock protein 47 levels that were measured on Day 0, while TGF alone elicited an increase in smooth muscle a-actin and heat shock protein 47 compared to Day 0 levels. Null treatment revealed diminished proteins at both time points. Conclusions: Elevated transforming growth factor-beta 1 levels, in the presence of cyclic mechanical tension, resulted in synergistic increases in contractile and biosynthetic proteins in aortic valve interstitial cells. Since cyclic mechanical stimuli can never be relieved in vivo, the presence of transforming growth factor-beta 1 (possibly from infiltrating macrophages) may result in overly biosynthetic aortic valve interstitial cells, leading to altered extracellular matrix architecture, compromised valve function, and, ultimately, degenerative valvular disease. (C) 2007 Elsevier Inc. All rights reserved.
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