Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK

1 Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Higashijima, Niigata City, Japan; 2 Departments of Cell Biology and Physiology, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri; and 3 First Department of Medicine, Niigata University School of Medicine, Niigata City, Japan Submitted 29 May 2006 ; accepted in final form 9 October 2006 It is generally believed that a mechanical signal initiates a cascade of biological events leading to coordinated cardiac remodeling. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. To evaluate the molecular mechanism underlying swimming stress-induced cardiac remodeling, we examined the role of 14-3-3 protein and MAPK pathway by pharmacological and genetic means using transgenic mice with cardiac-specific expression of dominant-negative (DN) mutants of 14-3-3 (DN 14-3-3/TG) and p38 / MAPK (DNp38 and DNp38 ) mice. p38 MAPK activation was earlier, more marked, and longer in the myocardium of the TG group compared with that of the nontransgenic (NTG) group after swimming stress, whereas JNK activation was detected on day 5 and decreased afterward. In contrast, ERK1/2 was not activated after swimming stress in either group. Cardiomyocyte apoptosis, cardiac hypertrophy, and fibrosis were greatly increased in the TG group compared with those in the NTG group. Moreover, we found a significant correlation between p38 MAPK activation and apoptosis in the TG group. Furthermore, DN 14-3-3 hearts showed enhanced atrial natriuretic peptide expression. In contrast, DNp38 and DNp38 mice exhibited reduced mortality and increased resistance to cardiac remodeling after 28 days of swimming stress compared with TG and NTG mice. Besides, treatment with a p38 MAPK inhibitor, FR-167653, resulted in regression of cardiac hypertrophy and fibrosis and improvement in the survival rate in the TG group. These results indicate for the first time that 14-3-3 protein along with p38 MAPK plays a crucial role in left ventricular remodeling associated with swimming stress. 14-3-3 protein; intracellular signal transduction; mechanical overload; transferase-mediated dUTP nick-end labeling; cardiac hypertrophy and fibrosis Address for reprint requests and other correspondence: K. Watanabe, Dept. of Clinical Pharmacology, Niigata Univ. of Pharmacy and Applied Life Sciences,