Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis

Basic Res Cardiol. 2010 Sep;105(5):573-81. doi: 10.1007/s00395-010-0106-3. Epub 2010 May 30.


Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested whether cardiac-specific overexpression of a constitutively active (T35D, AA 1-65) inhibitor-1 (I-1c), could also affect cardiac apoptosis and heart failure progression induced by prolonged beta-adrenergic stimulation. We found that either acute or chronic expression of I-1c reduced isoproterenol (ISO)-induced apoptosis assessed by nuclear condensation, TUNEL staining and DNA fragmentation. The beneficial effects of I-1c were associated with increased expression of the anti-apoptotic protein Bcl-2, decreased expression of the pro-apoptotic protein Bax and reduced levels of active caspases as well as increased activation of ERK. These findings suggest that mitochondrial signaling and ERK activation may be involved in the I-1c cardioprotective effects against apoptosis induced by prolonged beta-adrenergic stimulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic / physiology
  • Heart Failure / metabolism*
  • Heart Failure / pathology*
  • Heart Failure / physiopathology
  • Isoproterenol / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Phosphatase 1
  • Rats
  • Rats, Sprague-Dawley
  • bcl-Associated Death Protein / metabolism


  • Adrenergic beta-Agonists
  • Bad protein, mouse
  • Bad protein, rat
  • Phosphoproteins
  • Ppp1r1c protein, mouse
  • bcl-Associated Death Protein
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Phosphatase 1
  • Isoproterenol