Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis.
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.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575, USA.
Guoli
G
Chen
Xiaoyang
X
Zhou
Stela
S
Florea
Jiang
J
Qian
Wenfeng
W
Cai
Zhiguo
Z
Zhang
Guo-Chang
GC
Fan
John
J
Lorenz
Roger J
RJ
Hajjar
Evangelia G
EG
Kranias
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000318:Adrenergic beta-Agonists; C494820:Bad protein, mouse; C494821:Bad protein, rat; D010750:Phosphoproteins; C424983:Ppp1r1c protein, mouse; D051025:bcl-Associated Death Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D054645:Protein Phosphatase 1; D007545:Isoproterenol