TNF-alpha-mediated signal transduction pathway is a major determinant of apoptosis in dilated cardiomyopathy.
Although J2N-k strain of cardiomyopathic hamsters is an excellent model of dilated cardiomyopathy, the presence and mechanisms of apoptosis in the hearts of these genetically modified animals have not been investigated. This study examined the hypothesis that cardiac dysfunction and apoptosis in the cardiomyopathic hamsters were associated with tumour necrosis factor-alpha (TNF-alpha)-mediated signalling pathway involving the activation of some pro-apoptotic proteins and/or deactivation of some antiapoptotic proteins. Echocardiographic assessment of 31-week-old hamsters indicated an increase in the internal dimension of the left ventricle as well as decreases in the ejection fraction, fractional shortening and cardiac output without any evidence of cardiac hypertrophy. Increased level of TNF-alpha and apoptosis in cardiomyopathic hearts were accompanied by increased protein content for protein kinase C (PKC) -alpha and -epsilon isozymes as well as caspases 3 and 9. Phosphorylated protein content for p38 MAPK and NF kappaB was increased whereas that for Erk1/2, BAD and Bcl-2 was decreased in cardiomyopathic hearts. These results support the view that TNF-alpha and PKC isozymes may promote apoptosis due to the activation of p38 MAPK and deactivation of Erk1/2 pathways, and these changes may contribute toward the development of cardiac dysfunction in dilated cardiomyopathy.
Das
Samarjit
S
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Babick
Andrea P
AP
Xu
Yan-Jun
YJ
Takeda
Nobuakira
N
Rodriguez-Levya
Delfin
D
Dhalla
Naranjan S
NS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D006224:Cricetinae; D008297:Male; D015398:Signal Transduction / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D016211:Transforming Growth Factor alpha