Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1.
The ras family of small GTP-binding proteins exerts powerful effects upon cell structure and function. One member of this family, rac, induces actin cytoskeletal reorganization in nonmuscle cells and hypertrophic changes in cultured cardiomyocytes. To examine the effect of rac1 activation upon cardiac structure and function, transgenic mice were created that express constitutively activated rac1 specifically in the myocardium. Transgenic rac1 protein was expressed at levels comparable to endogenous rac levels, with activation of the rac1 signaling pathway resulting in two distinct cardiomyopathic phenotypes: a lethal dilated phenotype associated with neonatal activation of the transgene and a transient cardiac hypertrophy seen among juvenile mice that resolved with age. Neither phenotype showed myofibril disarray and hypertrophic hearts were hypercontractilein working heart analyses. The rac1 target p21-activated kinase translocated from a cytosolic to a cytoskeletal distribution, suggesting that rac1 activation was inducing focal adhesion reorganization. Corroborating results showed altered localizations of src in dilated cardiomyopathy and paxillin in both cardiomyopathic phenotypes. This study, the first examination of rac1-mediated cardiac effects in vivo, demonstrates that dilation and hypertrophy can share a common molecular origin and presents evidence that both timing and concurrent signaling from multiple pathways can influence cardiac remodeling.
Sussman
M A
MA
The Children's Hospital and Research Foundation, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio 45229, USA. sussman@heart.chmcc.org
Welch
S
S
Walker
A
A
Klevitsky
R
R
Hewett
T E
TE
Price
R L
RL
Schaefer
E
E
Yager
K
K
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D015870:Gene Expression; D006321:Heart; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D020830:rac1 GTP-Binding Protein