Alterations in apoptosis regulatory factors during hypertrophy and heart failure.
Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.
Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave., SL-423C, Boston, MA 02215, USA. pkang@bidmc.harvard.edu
Peter M
PM
Kang
Patrick
P
Yue
Zhilin
Z
Liu
Oleg
O
Tarnavski
Natalya
N
Bodyak
Seigo
S
Izumo
D000818:Animals; D017209:Apoptosis; D002303:Cardiac Output, Low / Q000209:etiology / Q000503:physiopathology*; D006332:Cardiomegaly / Q000150:complications / Q000209:etiology / Q000503:physiopathology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart; D009043:Motor Activity; D032383:Myocytes, Cardiac / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000009:adverse effects
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D020169:Caspases