Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease.
Matrix metalloproteinases (MMPs) and cathepsins are proteolytic enzymes that are upregulated in diseased aortic valve cusps. The objective of this study was to investigate whether elevated cyclic stretch causes an increased expression and activity of these proteolytic enzymes in the valve cusp. Circumferentially oriented fresh porcine aortic valve cusp sections were stretched to 10% (physiological), 15% (pathological), and 20% (hyperpathological) in a tensile stretch bioreactor for 24 and 48 h. The expression and activity of MMP-1, MMP-2, MMP-9, tissue inhibitor of MMP-1, and cathepsin L, S, and K were quantified and compared with fresh controls. Cell proliferation and apoptosis were also analyzed. As a result, at 10% physiological stretch, the expression and activity of remodeling enzymes were comparable with fresh controls. At 15% stretch, the expression of MMP-1, -2, -9 and cathepsin S and K were upregulated, whereas the expression of cathepsin L was downregulated compared with controls. A similar trend was observed at 20% stretch, but the magnitudes of upregulation and downregulation of the expression were less than those observed at 15%. In addition, there were significantly higher cell proliferation and apoptosis at 20% stretch compared with those of other treatment groups. In conclusion, elevated mechanical stretch on aortic valve cusps may detrimentally alter the proteolytic enzyme expression and activity in valve cells. This may trigger a cascade of events leading to an accelerated valve degeneration and disease progression.
Balachandran
Kartik
K
The Wallace H. Coulter School of Biomedical Engineering, Georgia Inst. of Technology, 313 Ferst Dr., Ste. 1121, Atlanta, GA 30332-0535, USA.
Sucosky
Philippe
P
Jo
Hanjoong
H
Yoganathan
Ajit P
AP
D000818:Animals; D001021:Aortic Valve / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D019149:Bioreactors; D002403:Cathepsins / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006349:Heart Valve Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D009924:Organ Culture Techniques; D010641:Phenotype; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D002403:Cathepsins; D053505:Matrix Metalloproteinases, Secreted