Journal of Molecular Medicine

, Volume 87, Issue 3, pp 249–260

Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3β signaling

  • Qizhu Tang
  • Jun Cai
  • Difei Shen
  • Zhouyan Bian
  • Ling Yan
  • You-Xin Wang
  • Jie Lan
  • Guo-Qing Zhuang
  • Wen-Zhan Ma
  • Wei Wang
Original Article

Abstract

The lysosomal cysteine peptidase cathepsin L (CTSL) is an important lysosomal proteinase involved in a variety of cellular functions including intracellular protein turnover, epidermal homeostasis, and hair development. Deficiency of CTSL in mice results in a progressive dilated cardiomyopathy. In the present study, we tested the hypothesis that cardiac overexpression of human CTSL in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human CTSL expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding (AB) in CTSL transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by two-dimensional and M-mode echocardiography as well as by molecular and pathological analyses of heart samples. Constitutive overexpression of human CTSL in the murine heart attenuated the hypertrophic response, markedly reduced apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased CTSL levels in response to hypertrophic stimuli. These beneficial effects were associated with attenuation of the Akt/GSK3β signaling cascade. Our in vitro studies further confirmed that CTSL expression in cardiomyocytes blunts cardiac hypertrophy through blocking of Akt/GSK3β signaling. The study indicates that CTSL improves cardiac function and inhibits cardiac hypertrophy, inflammation, and fibrosis through blocking Akt/GSK3β signaling.

Keywords

Cathepsin L cardiac remodeling AKT Fibrosis GSK3β 

Supplementary material

109_2008_423_MOESM1_ESM.pdf (1.3 mb)
ESM Fig. 1 (PDF 1.31 MB)

References

  1. 1.
    Palermo C, Joyce JA (2008) Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci 29:22–28PubMedCrossRefGoogle Scholar
  2. 2.
    Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S (2007) Cathepsin cysteine proteases in cardiovascular disease. FASEB J 21:3029–3041PubMedCrossRefGoogle Scholar
  3. 3.
    Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B (2007) Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 13:387–403PubMedCrossRefGoogle Scholar
  4. 4.
    Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6:764–775PubMedCrossRefGoogle Scholar
  5. 5.
    Reinheckel T, Deussing J, Roth W, Peters C (2001) Towards specific functions of lysosomal cysteine peptidases: phenotypes of mice deficient for cathepsin B or cathepsin L. Biol Chem 382:735–741PubMedCrossRefGoogle Scholar
  6. 6.
    Ohashi K, Naruto M, Nakaki T, Sano E (2003) Identification of interleukin-8 converting enzyme as cathepsin L. Biochim Biophys Acta 1649:30–39PubMedGoogle Scholar
  7. 7.
    Huang X, Vaag A, Carlsson E, Ahrén B, Groop L (2003) Impaired cathepsin L gene expression in skeletal muscle is associated with type 2 diabetes. Diabetes 52:2411–2418PubMedCrossRefGoogle Scholar
  8. 8.
    Sever S, Altintas MM, Nankoe SR, Möller CC, Ko D, Wei C, Henderson J, del Re EC, Hsing L, Erickson A, Cohen CD, Kretzler M, Kerjaschki D, Rudensky A, Nikolic B, Reiser J (2007) Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest 117:2095–2104PubMedCrossRefGoogle Scholar
  9. 9.
    Kitamoto S, Sukhova GK, Sun J, Yang M, Libby P, Love V, Duramad P, Sun C, Zhang Y, Yang X, Peters C, Shi GP (2007) Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115:2065–2075PubMedCrossRefGoogle Scholar
  10. 10.
    Stypmann J, Gläser K, Roth W, Tobin DJ, Petermann I, Matthias R, Mönnig G, Haverkamp W, Breithardt G, Schmahl W, Peters C, Reinheckel T (2002) Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc Natl Acad Sci U S A 99:6234–6239PubMedCrossRefGoogle Scholar
  11. 11.
    Petermann I, Mayer C, Stypmann J, Biniossek ML, Tobin DJ, Engelen MA, Dandekar T, Grune T, Schild L, Peters C, Reinheckel T (2006) Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice. FASEB J 20:1266–1268PubMedCrossRefGoogle Scholar
  12. 12.
    Spira D, Stypmann J, Tobin DJ, Petermann I, Mayer C, Hagemann S, Vasiljeva O, Günther T, Schüle R, Peters C, Reinheckel T (2008) Cell type-specific functions of the lysosomal protease cathepsin L in the heart. J Biol Chem 282:37045–3752CrossRefGoogle Scholar
  13. 13.
    Li HL, Liu C, de Couto G, Ouzounian M, Sun M, Wang AB, Huang Y, He CW, Shi Y, Chen X, Nghiem MP, Liu Y, Chen M, Dawood F, Fukuoka M, Maekawa Y, Zhang L, Leask A, Ghosh AK, Kirshenbaum LA, Liu PP (2008) Curcumin prevents and reverses murine cardiac hypertrophy. J Clin Invest 118:879–893PubMedCrossRefGoogle Scholar
  14. 14.
    Haudek SB, Taffet GE, Schneider MD, Mann DL (2007) TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 117:2692–2701PubMedCrossRefGoogle Scholar
  15. 15.
    Li HL, Huang Y, Zhang CN, Williams GM, Liu DP, Liang CC (2006) Epigallocathechin-3 gallate inhibits cardiac hypertrophy through blocking reactive oxidative species-dependent and -independent signal pathways. Free Radic Biol Med 40:1756–1775PubMedCrossRefGoogle Scholar
  16. 16.
    Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600PubMedCrossRefGoogle Scholar
  17. 17.
    Shiojima I, Walsh K (2006) Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 20:3347–3365PubMedCrossRefGoogle Scholar
  18. 18.
    DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ (2006) Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281:32841–32851PubMedCrossRefGoogle Scholar
  19. 19.
    Sugden PH, Fuller SJ, Weiss SC, Clerk A (2008) Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis. Br J Pharmacol 153:S137–S153PubMedCrossRefGoogle Scholar
  20. 20.
    Wang Y (2007) Mitogen-activated protein kinases in heart development and diseases. Circulation 116:1413–1423PubMedCrossRefGoogle Scholar
  21. 21.
    Molkentin JD (2004) Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63:467–475PubMedCrossRefGoogle Scholar
  22. 22.
    Leask A (2007) TGFbeta, cardiac fibroblasts, and the fibrotic response. Cardiovasc Res 74:207–212PubMedCrossRefGoogle Scholar
  23. 23.
    Van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ (2005) Myocyte apoptosis in heart failure. Cardiovasc Res 67:21–29PubMedCrossRefGoogle Scholar
  24. 24.
    Rutschow S, Li J, Schultheiss HP, Pauschinger M (2006) Myocardial proteases and matrix remodeling in inflammatory heart disease. Cardiovasc Res 69:646–656PubMedCrossRefGoogle Scholar
  25. 25.
    Li HL, She ZG, Li TB, Wang AB, Yang Q, Wei YS, Wang YG, Liu DP (2007) Overexpression of myofibrillogenesis regulator-1 aggravates cardiac hypertrophy induced by angiotensin II in mice. Hypertension. 49(6):1399–1408PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Qizhu Tang
    • 1
  • Jun Cai
    • 2
    • 3
  • Difei Shen
    • 1
  • Zhouyan Bian
    • 1
  • Ling Yan
    • 1
  • You-Xin Wang
    • 4
    • 5
  • Jie Lan
    • 4
    • 5
  • Guo-Qing Zhuang
    • 4
    • 5
  • Wen-Zhan Ma
    • 4
    • 5
  • Wei Wang
    • 4
    • 5
  1. 1.Cardiovascular Research Institute of Wuhan University and Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPeople’s Republic of China
  2. 2.Cardiovascular Research CenterMassachusettes General Hospital, Harvard Medical SchoolCharlestownUSA
  3. 3.Department of Cardiology, Beijing Chaoyang HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  4. 4.Graduate School of Chinese Academy of SciencesBeijingPeople’s Republic of China
  5. 5.School of Public Health and Family MedicineCapital Medical UniversityBeijingPeople’s Republic of China

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