title: Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast.
abstract: 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-beta1 would alter the phenotype and subsequent collagen biosynthesis of aortic valve interstitial cells in situ.
  
  
  RESULTS
  Porcine aortic valve leaflets received 7- and 14-day treatments of 15% cyclic stretch (Tension); 0.5 ng/ml transforming growth factor-beta1 (TGF); 15% cyclic stretch and 0.5 ng/ml transforming growth factor-beta1 (Tension+TGF); or neither mechanical nor cytokine stimuli (Null). Tissues were homogenized and assayed for aortic valve interstitial cell phenotype (smooth muscle alpha-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, heat 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 alpha-actin and heat shock protein 47 levels that were measured on Day 0, while TGF alone elicited an increase in smooth muscle alpha-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-beta1 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-beta1 (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.
authors.affiliation: Engineered Tissue Mechanics Laboratory, Department of Bioengineering and the McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
authors.forename: Howard D
authors.initials: HD
authors.lastname: Lukoff
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Long
authors.forename: George C
authors.initials: GC
authors.lastname: Engelmayr
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hopkins
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sacks
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism*; D019149:Bioreactors; D024042:Collagen Type I / Q000096:biosynthesis; D004867:Equipment Design; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D050958:HSP47 Heat-Shock Proteins / Q000096:biosynthesis; D010641:Phenotype; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D046509:Tissue Culture Techniques; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000199:Actins; D024042:Collagen Type I; D050958:HSP47 Heat-Shock Proteins; D053773:Transforming Growth Factor beta1