Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes

Can J Physiol Pharmacol. 2018 Dec;96(12):1238-1245. doi: 10.1139/cjpp-2018-0275. Epub 2018 Oct 11.


Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 μM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions.

Keywords: cardiac myocyte; doxorubicin; doxorubicine; matrix metalloproteinase; myocyte cardiaque; métalloprotéinase matricielle; oxidative stress; sarcomere; stress oxydatif.

MeSH terms

  • Aconitate Hydratase / metabolism
  • Actinin / metabolism
  • Animals
  • Down-Regulation / drug effects
  • Doxorubicin / pharmacology*
  • Hydroxamic Acids / pharmacology
  • Matrix Metalloproteinase 2 / metabolism*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Oxidative Stress / drug effects
  • Phenyl Ethers / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sulfones / pharmacology
  • Troponin I / metabolism
  • Up-Regulation / drug effects


  • Hydroxamic Acids
  • N-hydroxy-2-((4-phenylphenyl)sulfonylpropan-2-yloxyamino)acetamide
  • N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide
  • Phenyl Ethers
  • RNA, Messenger
  • Sulfones
  • Troponin I
  • Actinin
  • Doxorubicin
  • Matrix Metalloproteinase 2
  • Aconitate Hydratase