Skip to main content
SpringerLink
Log in

Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Transition from compensated to decompensated left ventricular hypertrophy (LVH) is accompanied by functional and structural changes. Here, the aim was to evaluate dystrophin expression in murine models and human subjects with LVH by transverse aortic constriction (TAC) and aortic stenosis (AS), respectively. We determined whether doxycycline (Doxy) prevented dystrophin expression and myocardial stiffness in mice. Additionally, ventricular function recovery was evaluated in patients 1 year after surgery. Mice were subjected to TAC and monitored for 3 weeks. A second group received Doxy treatment after TAC. Patients with AS were stratified by normal left ventricular end-diastolic wall stress (LVEDWS) and high LVEDWS, and groups were compared. In mice, LVH decreased inotropism and increased myocardial stiffness associated with a dystrophin breakdown and a decreased mitochondrial O2 uptake (MitoMVO2). These alterations were attenuated by Doxy. Patients with high LVEDWS showed similar results to those observed in mice. A correlation between dystrophin and myocardial stiffness was observed in both mice and humans. Systolic function at 1 year post-surgery was only recovered in the normal-LVEDWS group. In summary, mice and humans present diastolic dysfunction associated with dystrophin degradation. The recovery of ventricular function was observed only in patients with normal LVEDWS and without dystrophin degradation. In mice, Doxy improved MitoMVO2. Based on our results it is concluded that the LVH with high LVEDWS is associated to a degradation of dystrophin and increase of myocardial stiffness. At least in a murine model these alterations were attenuated after the administration of a matrix metalloprotease inhibitor.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Hein S, Kostin S, Heling A, Maeno Y, Schaper J (2000) The role of the cytoskeleton in heart failure. Cardiovasc Res 45:273–278. doi:10.1016/S0008-6363(99)00268-0

    Article  CAS  PubMed  Google Scholar 

  2. Toyo-Oka T, Kawada T, Nakata J, Xie H, Urabe M, Masui F, Ebisawa T, Tezuka A, Iwasawa K, Nakajima T, Uehara Y, Kumagai H, Kostin S, Schaper J, Nakazawa M, Ozawa K (2004) Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure: a scheme for the progression of cardiac dysfunction. Proc Natl Acad Sci USA 101:7381–7385. doi:10.1073/pnas.0401944101

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kawada T, Masui F, Tezuka A, Ebisawa T, Kumagai H, Nakazawa M, Toyo-Oka T (2005) A novel scheme of dystrophin disruption for the progression of advanced heart failure. Biochim Biophys 1751:73–81. doi:10.1016/j.bbapap.2005.01.001

    Article  CAS  Google Scholar 

  4. Townsend D, Turner I, Yasuda S, Martindale J, Davis J, Shillingford M, Kornegay JN, Metzger JM (2010) Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs. J Clin Investig 120:1140–1150. doi:10.1172/JCI41329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Townsend D, Yasuda S, McNally E, Metzger JM (2011) Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. FASEB J 25:3106–3114. doi:10.1096/fj.10-178913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Han F, Lu YM, Hasegawa H, Kanai H, Hachimura E, Shirasaki Y, Fukunaga K (2010) Inhibition of dystrophin breakdown and endothelial nitric-oxide synthase uncoupling accounts for cytoprotection by 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e) in left ventricular hypertrophied mice. J Pharmacol Exp Ther 332:421–428. doi:10.1124/jpet.109.161646

    Article  CAS  PubMed  Google Scholar 

  7. Buchholz B, Perez V, Siachoque N, Miksztowicz V, Berg G, Rodríguez M, Donato M, Gelpi RJ (2014) Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning. Am J Physiol Heart Circ Physiol 307:88–96. doi:10.1152/ajpheart.00242.2013

    Article  Google Scholar 

  8. Yarbrough WM, Mukherjee R, Ikonomidis JS, Zile MR, Spinale FG (2012) Myocardial remodeling with aortic stenosis and after aortic valve replacement: mechanisms and future prognostic implications. J Thorac Cardiovasc Surg 143:656–664. doi:10.1016/j.jtcvs.2011.04.044

    Article  PubMed  Google Scholar 

  9. Sahn DJ, DeMaria A, Kisslo J, Weyman A (1978) Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58:1072–1083. doi:10.1161/01.CIR.58.6.1072

    Article  CAS  PubMed  Google Scholar 

  10. Errami M, Galindo CL, Tassa AT, Dimaio JM, Hill JA, Garner HR (2008) Doxycycline attenuates isoproterenol and transverse aortic banding-induced cardiac hypertrophy in mice. J Pharmacol Exp Ther 324:1196–1203. doi:10.1124/jpet.107.133975

    Article  CAS  PubMed  Google Scholar 

  11. Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J (2003) Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation 108:1487–1492. doi:10.1161/01.CIR.0000089090.05757.34

    Article  CAS  PubMed  Google Scholar 

  12. Wang G, Bergman M, Nguyen A, Turcato S, Swigart P, Rodrigo M, Simpson PC, Karliner JS, Lovett DH, Baker AJ (2006) Cardiac transgenic matrix metalloproteinase-2 expression directly induces impaired contractility. Cardiovasc Res 69:688–696. doi:10.1016/j.cardiores.2005.08.023

    Article  CAS  PubMed  Google Scholar 

  13. Rork TH, Hadzimichalis NM, Kappil MA, Merrill GF (2006) Acetaminophen attenuates peroxynitrite-activated matrix metalloproteinase-2-mediated troponin I cleavage in the isolated guinea pig myocardium. J Mol Cell Cardiol 40:553–561. doi:10.1016/j.yjmcc.2006.01.010

    Article  CAS  PubMed  Google Scholar 

  14. Sawicki G, Leon H, Sawicka J, Sariahmetoglu M, Schulze CJ, Scott PG, Szczesna-Cordary D, Schulz R (2005) Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation 112:544–552. doi:10.1161/CIRCULATIONAHA.104.531616

    Article  CAS  PubMed  Google Scholar 

  15. Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG, Weber KT (1989) Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64:1041–1050. doi:10.1161/01.RES.64.6.1041

    Article  CAS  PubMed  Google Scholar 

  16. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H (2006) Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47:711–717. doi:10.1161/01.HYP.0000208840.30778.00

    Article  CAS  PubMed  Google Scholar 

  17. Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OH (1995) Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 91:161–170. doi:10.1161/01.CIR.91.1.161

    Article  CAS  PubMed  Google Scholar 

  18. Gelpi RJ, Gao S, Zhai P, Yan L, Hong C, Danridge LM, Ge H, Maejima Y, Donato M, Yokota M, Molkentin JD, Vatner DE, Vatner SF, Sadoshima J (2009) Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload. Am J Physiol Heart Circ Physiol 297:1814–1819. doi:10.1152/ajpheart.00449.2009

    Article  Google Scholar 

  19. Stuyvers BD, Miura M, ter Keurs HE (2000) Ca (2+) dependence of passive properties of cardiac sarcomeres. Adv Exp Med Biol 481:353–366

    Article  CAS  PubMed  Google Scholar 

  20. Akhmedov AT, Rybin V, Marín-García J (2015) Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart. Heart Fail Rev 20:227–249. doi:10.1007/s10741-014-9457-4

    Article  CAS  PubMed  Google Scholar 

  21. Zhou LY, Liu JP, Wang K, Gao J, Ding SL, Jiao JQ, Li PF (2013) Mitochondrial function in cardiac hypertrophy. Int J Cardiol 167:1118–1125. doi:10.1016/j.ijcard.2012.09.082

    Article  PubMed  Google Scholar 

  22. Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101:1833–1839 doi:10.1161/01.CIR.101.15.1833

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Liliana Grinfeld for assistance in recruiting patients in the control group and for additional invaluable support.

Author information

Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina

    Martín Donato, Bruno Buchholz, Celina Morales, Diamela T. Paez, Mirian Matoso & Ricardo J. Gelpi

  2. School of Pharmacy and Biochemistry, Institute of Biochemistry and Molecular Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina

    Laura Valdez, Tamara Zaobornyj & Alberto Boveris

  3. Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina

    Sergio Baratta, Guillermo Vaccarino, Demian Chejtman, Oscar Agüero, Juan Telayna, José Navia & Alejandro Hita

Authors
  1. Martín Donato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Buchholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Celina Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Valdez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tamara Zaobornyj
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sergio Baratta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diamela T. Paez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mirian Matoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guillermo Vaccarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Demian Chejtman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Oscar Agüero
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Juan Telayna
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. José Navia
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alejandro Hita
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alberto Boveris
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ricardo J. Gelpi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo J. Gelpi.

Ethics declarations

Conflict of interest

none declared.

Additional information

Martín Donato, Bruno Buchholz, Laura Valdez, Tamara Zaobornyj, Alberto Boveris, and Ricardo J. Gelpi are members of the National Council of Scientific and Technological Research (CONICET).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donato, M., Buchholz, B., Morales, C. et al. Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy. Mol Cell Biochem 432, 169–178 (2017). https://doi.org/10.1007/s11010-017-3007-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3007-z

Keywords

Search

Navigation