Cardiomyocyte cell cycle activation ameliorates fibrosis in the atrium.
MHC-TGFcys33ser transgenic mice have elevated levels of active transforming growth factor (TGF)-beta1 in the myocardium. Previous studies have shown that these animals develop atrial, but not ventricular, fibrosis. Here we show that atrial fibrosis was accompanied with cardiomyocyte apoptosis. Although similar levels of cardiomyocyte apoptosis were present in the right and left atria of MHC-TGFcys33ser hearts, the extent of fibrosis was more pronounced in the right atrium. Thus, additional factors influence the degree of atrial fibrosis in this model. Tritiated thymidine incorporation studies revealed cardiomyocyte cell cycle activity in left atrial cardiomyocytes, but not in right atrial cardiomyocytes. These observations suggested that cardiomyocyte cell cycle activation ameliorated the severity of atrial fibrosis. To directly test this hypothesis, MHC-TGFcys33ser mice were crossed with MHC-cycD2 mice (which have constitutive cardiomyocyte cell cycle activity in the right atrium). Mice inheriting both transgenes exhibited right atrial cardiomyocyte cell cycle activity and a concomitant reduction in the severity of right atrial fibrosis, despite the presence of a similar level of cardiomyocyte apoptosis as was observed in mice inheriting the MHC-TGFcys33ser transgene alone. These data support the notion that cardiomyocyte cell cycle induction can antagonize fibrosis in the myocardium.
Nakajima
Hidehiro
H
Herman B Wells Center for Pediatric Research, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Nakajima
Hisako O
HO
Dembowsky
Klaus
K
Pasumarthi
Kishore B S
KB
Field
Loren J
LJ
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA