Skip to main content
SpringerLink
Log in

Strain effects on collagen proteolysis in heart valve tissues

  • Published:
Mechanics of Time-Dependent Materials Aims and scope Submit manuscript

Abstract

Collagen is at the heart of any and all questions concerning semilunar valvular leaflet composition, structure, and function. Whether during development, physiological homeostasis, or pathological degeneration, it is the structural-mechanical state of the heart valve leaflet collagen network that ultimately confers valvular function, and the difference between health and disease. In the current study, the effects of physiologically relevant strain states on collagen catabolism are investigated in porcine aortic and pulmonary valve leaflets. Application of bacterial collagenase to the tissues which acts to simulate collagen degradation by endogenous matrix metalloproteinases, biaxial stress relaxation, and histology are all used to serve as measures of functional and compositional collagen catabolism. Current stress-relaxation results are used in conjunction with previous equibiaxial testing to confirm that a mechanism exists to prevent collagen catabolism when stretched at physiologically relevant strain states. Collectively, these in vitro results indicate that biaxial strain states are capable of impacting the susceptibility of valvular collagens to catabolism, and that at physiological strain states, a protective mechanism exists to effectively block collagen catabolism. The results of the study will be broadly applicable to clarify the roles of tissue microarchitecture and load transmission in a variety of other developmental, homeostatic, or pathogenic tissue processes such as tumor growth, embryogenesis, thrombi formation, and atherogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Adhikari, A.S., Chai, J., Dunn, A.R.: Mechanical load induces a 100-fold increase in the rate of collagen proteolysis by MMP-1. J. Am. Chem. Soc. 133(6), 1686–1689 (2011). https://doi.org/10.1021/ja109972p

    Article  Google Scholar 

  • Aldous, I.G., Veres, S.P., Jahangir, A., Lee, J.M.: Differences in collagen cross-linking between the four valves of the bovine heart: a possible role in adaptation to mechanical fatigue. Am. J. Physiol., Heart Circ. Physiol. 296(6), 1898–1906 (2009). https://doi.org/10.1152/ajpheart.01173.2008

    Article  Google Scholar 

  • Anssari-Benam, A., Bader, D.L., Screen, H.R.: Anisotropic time-dependant behaviour of the aortic valve. J. Mech. Behav. Biomed. Mater. 4(8), 1603–1610 (2011). https://doi.org/10.1016/j.jmbbm.2011.02.010

    Article  Google Scholar 

  • Anssari-Benam, A., Gupta, H.S., Screen, H.R.C.: Strain transfer through the aortic valve. J. Biomech. Eng. 134(6), 061003 (2012). https://doi.org/10.1115/1.4006812

    Article  Google Scholar 

  • Balachandran, K., Konduri, S., Sucosky, P., Jo, H., Yoganathan, A.P.: An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Ann. Biomed. Eng. 34(11), 1655–1665 (2006). https://doi.org/10.1007/s10439-006-9167-8

    Article  Google Scholar 

  • Balachandran, K., Sucosky, P., Jo, H., Yoganathan, A.P.: Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am. J. Physiol., Heart Circ. Physiol. 296(3), H756 (2009). https://doi.org/10.1152/ajpheart.00900.2008

    Article  Google Scholar 

  • Banerjee, T., Mukherjee, S., Ghosh, S., Biswas, M., Dutta, S., Pattari, S., Chatterjee, S., Bandyopadhyay, A.: Clinical significance of markers of collagen metabolism in rheumatic mitral valve disease. PLoS ONE 9(3), e90527 (2014). https://doi.org/10.1371/journal.pone.0090527

    Article  Google Scholar 

  • Benjamin, E.J., Blaha, M.J., Chiuve, S.E., Cushman, M., Das, S.R., Deo, R., de Ferranti, S.D., Floyd, J., Fornage, M., Gillespie, C., Isasi, C.R., Jimenez, M.C., Jordan, L.C., Judd, S.E., Lackland, D., Lichtman, J.H., Lisabeth, L., Liu, S., Longenecker, C.T., Mackey, R.H., Matsushita, K., Mozaffarian, D., Mussolino, M.E., Nasir, K., Neumar, R.W., Palaniappan, L., Pandey, D.K., Thiagarajan, R.R., Reeves, M.J., Ritchey, M., Rodriguez, C.J., Roth, G.A., Rosamond, W.D., Sasson, C., Towfighi, A., Tsao, C.W., Turner, M.B., Virani, S.S., Voeks, J.H., Willey, J.Z., Wilkins, J.T., Wu, J.H., Alger, H.M., Wong, S.S., Muntner, P. (American Heart Association Statistics Committee and Stroke Statistics Subcommittee): Heart disease and Stroke statistics-2017 update: a report from the American Heart Association. Circulation 135(10), e146–e603 (2017). https://doi.org/10.1161/CIR.0000000000000485

    Article  Google Scholar 

  • Bhole, A.P., Flynn, B.P., Liles, M., Saeidi, N., Dimarzio, C.A., Ruberti, J.W.: Mechanical strain enhances survivability of collagen micronetworks in the presence of collagenase: implications for load-bearing matrix growth and stability. Philos. Trans. R. Soc., Math. Phys. Eng. Sci. 367(1902), 3339–3362 (2009). https://doi.org/10.1098/Rsta.2009.0093

    Article  Google Scholar 

  • Camp, R.J., Liles, M., Beale, J., Saeidi, N., Flynn, B.P., Moore, E., Murthy, S.K., Ruberti, J.W.: Molecular mechanochemistry: low force switch slows enzymatic cleavage of human type I collagen monomer. J. Am. Chem. Soc. 133(11), 4073–4078 (2011). https://doi.org/10.1021/Ja110098b

    Article  Google Scholar 

  • Carruthers, C.A., Alfieri, C.M., Joyce, E.M., Watkins, S.C., Yutzey, K.E., Sacks, M.S.: Gene expression and collagen fiber micromechanical interactions of the semilunar heart valve interstitial cell. Cell. Mol. Bioeng. 5(3), 254–265 (2012). https://doi.org/10.1007/s12195-012-0230-2

    Article  Google Scholar 

  • Chang, S.W., Flynn, B.P., Ruberti, J.W., Buehler, M.J.: Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown. Biomaterials 33(15), 3852–3859 (2012). https://doi.org/10.1016/j.biomaterials.2012.02.001

    Article  Google Scholar 

  • Cole, W.G., Chan, D., Hickey, A.J., Wilcken, D.E.: Collagen composition of normal and myxomatous human mitral heart valves. Biochem. J. 219(2), 451–460 (1984)

    Article  Google Scholar 

  • Ellsmere, J.C., Khanna, R.A., Lee, J.M.: Mechanical loading of bovine pericardium accelerates enzymatic degradation. Biomaterials 20(12), 1143–1150 (1999)

    Article  Google Scholar 

  • Flynn, B.P., Bhole, A.P., Saeidi, N., Liles, M., Dimarzio, C.A., Ruberti, J.W.: Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8). PLoS ONE 5(8), e12337 (2010). https://doi.org/10.1371/journal.pone.0012337

    Article  Google Scholar 

  • Flynn, B.P., Tilburey, G.E., Ruberti, J.W.: Highly sensitive single-fibril erosion assay demonstrates mechanochemical switch in native collagen fibrils. Biomech. Model. Mechanobiol. 12(2), 291–300 (2013). https://doi.org/10.1007/s10237-012-0399-2

    Article  Google Scholar 

  • Fondard, O., Detaint, D., Iung, B., Choqueux, C., Adle-Biassette, H., Jarraya, M., Hvass, U., Couetil, J.P., Henin, D., Michel, J.B., Vahanian, A., Jacob, M.P.: Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. Eur. Heart J. 26(13), 1333–1341 (2005). https://doi.org/10.1093/eurheartj/ehi248

    Article  Google Scholar 

  • Ghazanfari, S., Driessen-Mol, A., Bouten, C.V., Baaijens, F.P.: Modulation of collagen fiber orientation by strain-controlled enzymatic degradation. Acta Biomater. 35, 118–126 (2016). https://doi.org/10.1016/j.actbio.2016.02.033

    Article  Google Scholar 

  • Huang, S., Huang, H.-Y.S.: Biaxial stress relaxation of semilunar heart valve leaflets during simulated collagen catabolism: effects of collagenase concentration and equibiaxial strain-state. Proc. Inst. Mech. Eng., H J. Eng. Med. 229(10), 721–731 (2015). https://doi.org/10.1177/0954411915604336

    Article  Google Scholar 

  • Huang, C., Yannas, I.V.: Mechanochemical studies of enzymatic degradation of insoluble collagen-fibers. J. Biomed. Mater. Res. 11(1), 137–154 (1977). https://doi.org/10.1002/jbm.820110113

    Article  Google Scholar 

  • Huang, H.Y., Liao, J., Sacks, M.S.: In-situ deformation of the aortic valve interstitial cell nucleus under diastolic loading. J. Biomech. Eng. 129(6), 880 (2007). https://doi.org/10.1115/1.2801670

    Article  Google Scholar 

  • Huang, H.-Y.S., Balhouse, B.N., Huang, S.: Application of simple biomechanical and biochemical tests to heart valve leaflets: implications for heart valve characterization and tissue engineering. Proc. Inst. Mech. Eng., H J. Eng. Med. 226(H11), 868–876 (2012). https://doi.org/10.1177/0954411912455004

    Article  Google Scholar 

  • Huang, H.-Y.S., Huang, S., Frazier, C.P., Prim, P., Harrysson, O.: Directional mechanical property of porcine skin tissues. J. Mech. Med. Biol. 14(5), 1450069 (2014). https://doi.org/10.1142/S0219519414500699

    Article  Google Scholar 

  • Kheradvar, A., Groves, E.M., Dasi, L.P., Alavi, S.H., Tranquillo, R., Grande-Allen, K.J., Simmons, C.A., Griffith, B., Falahatpisheh, A., Goergen, C.J., Mofrad, M.R., Baaijens, F., Little, S.H., Canic, S.: Emerging trends in heart valve engineering: part I. Solutions for future. Ann. Biomed. Eng. 43(4), 833–843 (2015). https://doi.org/10.1007/s10439-014-1209-z

    Article  Google Scholar 

  • Lacerda, C.M., Maclea, H.B., Kisiday, J.D., Orton, E.C.: Static and cyclic tensile strain induce myxomatous effector proteins and serotonin in canine mitral valves. J. Vet. Cardiol. 14(1), 223–230 (2012). https://doi.org/10.1016/j.jvc.2011.12.002

    Article  Google Scholar 

  • Lewinsohn, A.D., Anssari-Benham, A., Lee, D.A., Taylor, P.M., Chester, A.H., Yacoub, M.H., Screen, H.R.: Anisotropic strain transfer through the aortic valve and its relevance to the cellular mechanical environment. Proc. Inst. Mech. Eng. H 225(8), 821–830 (2011)

    Article  Google Scholar 

  • Merryman, W.D., Lukoff, H.D., Long, R.A., Engelmayr, G.C. Jr., Hopkins, R.A., Sacks, M.S.: Synergistic effects of cyclic tension and transforming growth factor-\(\beta1\) on the aortic valve myofibroblast. Cardiovasc. Pathol. 16(5), 268–276 (2007). https://doi.org/10.1016/j.carpath.2007.03.006

    Article  Google Scholar 

  • Nabeshima, Y., Grood, E.S., Sakurai, A., Herman, J.H.: Uniaxial tension inhibits tendon collagen degradation by collagenase in vitro. J. Orthop. Res. 14(1), 123–130 (1996). https://doi.org/10.1002/jor.1100140120

    Article  Google Scholar 

  • NIH: Heart and Vascular Diseases. Report. National Heart Lung and Blood Institute (2016)

  • Perrotta, I., Sciangula, A., Aquila, S., Mazzulla, S.: Matrix metalloproteinase-9 expression in calcified human aortic valves: a histopathologic, immunohistochemical, and ultrastructural study. Appl. Immunohistochem. Mol. Morphol. (2014). https://doi.org/10.1097/PAI.0000000000000144

    Article  Google Scholar 

  • Rabkin, E., Aikawa, M., Stone, J.R., Fukumoto, Y., Libby, P., Schoen, F.J.: Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 104(21), 2525–2532 (2001)

    Article  Google Scholar 

  • Rabkin-Aikawa, E., Aikawa, M., Farber, M., Kratz, J.R., Garcia-Cardena, G., Kouchoukos, N.T., Mitchell, M.B., Jonas, R.A., Schoen, F.J.: Clinical pulmonary autograft valves: pathologic evidence of adaptive remodeling in the aortic site. J. Thorac. Cardiovasc. Surg. 128(4), 552–561 (2004). https://doi.org/10.1016/j.jtcvs.2004.04.016

    Article  Google Scholar 

  • Robitaille, M.C., Zareian, R., DiMarzio, C.A., Wan, K.T., Ruberti, J.W.: Small-angle light scattering to detect strain-directed collagen degradation in native tissue. Interface Focus 1(5), 767–776 (2011). https://doi.org/10.1098/rsfs.2011.0039

    Article  Google Scholar 

  • Rodriguez, K.J., Piechura, L.M., Porras, A.M., Masters, K.S.: Manipulation of valve composition to elucidate the role of collagen in aortic valve calcification. BMC Cardiovasc. Disord. 14(1), 29 (2014). https://doi.org/10.1186/1471-2261-14-29

    Article  Google Scholar 

  • Ruberti, J.W., Hallab, N.J.: Strain-controlled enzymatic cleavage of collagen in loaded matrix. Biochem. Biophys. Res. Commun. 336(2), 483–489 (2005). https://doi.org/10.1016/j.bbrc.2005.08.128

    Article  Google Scholar 

  • Sacks, M.S., Schoen, F.J.: Collagen fiber disruption occurs independent of calcification in clinically explanted bioprosthetic heart valves. J. Biomed. Mater. Res. 62(3), 359–371 (2002). https://doi.org/10.1002/jbm.10293

    Article  Google Scholar 

  • Sacks, M.S., Yoganathan, A.P.: Heart valve function: a biomechanical perspective. Philos. Trans. R. Soc. Lond. B, Biol. Sci. 362(1484), 1369–1391 (2007). https://doi.org/10.1098/rstb.2007.2122

    Article  Google Scholar 

  • Sacks, M.S., Smith, D.B., Hiester, E.D.: A small angle light scattering device for planar connective tissue microstructural analysis. Ann. Biomed. Eng. 25(4), 678–689 (1997)

    Article  Google Scholar 

  • Schoen, F.J.: Morphology, clinicopathologic correlations, and mechanisms in heart valve health and disease. Cardiovasc. Eng. Technol. (2016). https://doi.org/10.1007/s13239-016-0277-7

    Article  Google Scholar 

  • Schoen, F.J., Levy, R.J.: Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann. Thorac. Surg. 79(3), 1072–1080 (2005). https://doi.org/10.1016/j.athoracsur.2004.06.033

    Article  Google Scholar 

  • Stella, J.A., Liao, J., Sacks, M.S.: Time-dependent biaxial mechanical behavior of the aortic heart valve leaflet. J. Biomech. 40(14), 3169–3177 (2007). https://doi.org/10.1016/j.jbiomech.2007.04.001

    Article  Google Scholar 

  • Thubrikar, M., Piepgrass, W.C., Deck, J.D., Nolan, S.P.: Stresses of natural versus prosthetic aortic valve leaflets in vivo. Ann. Thorac. Surg. 30(3), 230–239 (1980)

    Article  Google Scholar 

  • Thubrikar, M.J., Skinner, J.R., Eppink, R.T., Nolan, S.P.: Stress analysis of porcine bioprosthetic heart valves in vivo. J. Biomed. Mater. Res. 16, 811–826 (1982)

    Article  Google Scholar 

  • Thubrikar, M.J., Deck, J.D., Aouad, J., Nolan, S.P.: Role of mechanical stress in calcification of aortic bioprosthetic valves. J. Thorac. Cardiovasc. Surg. 86(1), 115–125 (1983)

    Article  Google Scholar 

  • Thubrikar, M.J., Aouad, J., Nolan, S.P.: Comparison of the in vivo and in vitro mechanical properties of aortic valve leaflets. J. Thorac. Cardiovasc. Surg. 92(1), 29–36 (1986)

    Article  Google Scholar 

  • van der Kamp, A.W., Nauta, J.: Fibroblast function and the maintenance of the aortic-valve matrix. Cardiovasc. Res. 13(3), 167–172 (1979)

    Article  Google Scholar 

  • Wyatt, K.E.K., Bourne, J.W., Torzilli, P.A.: Deformation-dependent enzyme mechanokinetic cleavage of type I collagen. J. Biomech. Eng. 131(5), 051004 (2009). https://doi.org/10.1115/1.3078177

    Article  Google Scholar 

  • Yip, C.Y.Y., Simmons, C.A.: The aortic valve microenvironment and its role in calcific aortic valve disease. Cardiovasc. Pathol. 20(3), 177–182 (2011). https://doi.org/10.1016/j.carpath.2010.12.001

    Article  Google Scholar 

  • Yip, C.Y.Y., Chen, J.-H., Zhao, R., Simmons, C.A.: Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler. Thromb. Vasc. Biol. 29(6), 936–942 (2009). https://doi.org/10.1161/atvbaha.108.182394

    Article  Google Scholar 

  • Zareian, R., Church, K.P., Saeidi, N., Flynn, B.P., Beale, J.W., Ruberti, J.W.: Probing collagen/enzyme mechanochemistry in native tissue with dynamic, enzyme-induced creep. Langmuir 26(12), 9917–9926 (2010). https://doi.org/10.1021/la100384e

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mechanical and Aerospace Engineering Department, North Carolina State University, R3158 Engineering Building 3, 911 Oval Drive, Campus Box 7910, Raleigh, NC, 27695, USA

    Kaitlyn Barbour & Hsiao-Ying Shadow Huang

Authors
  1. Kaitlyn Barbour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hsiao-Ying Shadow Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hsiao-Ying Shadow Huang.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barbour, K., Huang, HY.S. Strain effects on collagen proteolysis in heart valve tissues. Mech Time-Depend Mater 24, 85–100 (2020). https://doi.org/10.1007/s11043-019-09410-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11043-019-09410-7

Keywords

Search

Navigation