Effects of beta-adrenoceptors overexpression on cell survival are mediated by Bax/Bcl-2 pathway in rat cardiac myocytes.
BACKGROUND
Chronic activation of beta-adrenoceptors (beta-ARs) results in cardiac myocyte injury, even death, and diminishes the number of beta-ARs.


OBJECTIVE
To investigate the effects of overexpression of beta(1)- or beta(2)-AR on cardiomyocytes injured by isoprenaline (ISO).


METHODS
We have used an adenoviral vector carrying the sequence for human beta(1)- or beta(2)-AR (Adv.beta(1), Adv.beta(2)) to increase the content of beta(1) or beta(2)-AR in isolated adult rat ventricular myocytes, and we have examined the cell survival and the expression of Bax and Bcl-2.


RESULTS
With use of adenoviral vectors, the beta(1)- and beta(2)-AR contents of myocytes were increased 2.98- and 2.87-fold, respectively. Overexpression of beta(1)-AR sharpened the cellular injury of ISO. If beta(2)-AR activity was further blocked by addition of selective beta(2)-AR antagonist ICI118,551, the cells were more sensitive to the impairment of Adv.beta(1) + ISO. Overexpression of Adv.beta(2) partially inversed the cytotoxicity of ISO stimulation. The beneficial effects were strengthened by addition of CGP20712A, a beta(1)-AR-blocking agent. Western blot analysis demonstrated that both increasing beta(1)-AR and inhibition of beta(2)-AR increased the ratio of Bax/Bcl-2. Whereas, increasing beta(2)-AR and inhibition of beta(1)-AR decreased the ratio of Bax/ Bcl-2. Control adenovirus CGP had no effect on cell survival.


CONCLUSIONS
Overexpression of Adv.beta(2) and/or inhibition of beta(1)-AR have protective effect on adult rat ventricular myocytes chronically stimulated by ISO. Overexpression of Adv.beta(1) and/or inhibition of beta(2)-AR are deleterious in the same state. The effects of beta-ARs on cell survival might be mediated by the Bax/Bcl-2 signal pathway.
Sun
Hong
H
Atherosclerosis Research Center, Nanjing Medical University, Nanjing, 210029 Jiangsu, PR China.
Zhou
Feng
F
Wang
Ying
Y
Zhang
Yang
Y
Chang
Aimin
A
Chen
Qi
Q
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis* / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C494828:Bax protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D051028:bcl-2-Associated X Protein; D007545:Isoproterenol