Role of 14-3-3-Mediated p38 Mitogen-Activated Protein Kinase Inhibition in Cardiac Myocyte Survival

• Published in: Circulation research 2003-11, Vol.93 (11), p.1026-1028
• Main Authors: Zhang, Shaosong, Ren, Jie, Zhang, Cindy E, Treskov, Ilya, Wang, Yibin, Muslin, Anthony J
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins; Animals; Aorta - physiology; Apoptosis - genetics; Biological and medical sciences; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - prevention & control; Cell Survival - drug effects; Cell Survival - genetics; Constriction, Pathologic; Crosses, Genetic; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genes, Dominant; Heart; Imidazoles - pharmacology; Injections, Intraperitoneal; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; p38 Mitogen-Activated Protein Kinases; Pyridines - pharmacology; Survival Rate; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000104084.88317.91

14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. Targeted expression of dominant-negative 14-3-3η (DN-14-3-3) to murine postnatal cardiac tissue potentiates Ask1, c-jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) activation. DN-14-3-3 mice are unable to compensate for pressure overload, which results in increased mortality, dilated cardiomyopathy, and cardiac myocyte apoptosis. To evaluate the relative role of p38 MAPK activity in the DN-14-3-3 phenotype, we inhibited cardiac p38 MAPK activity by pharmacological and genetic methods. Intraperitoneal injection of SB202190, an inhibitor of p38α and p38β MAPK activity, markedly increased the ability of DN-14-3-3 mice to compensate for pressure overload, with decreased mortality. DN-14-3-3 mice were bred with transgenic mice in which dominant-negative p38α (DN-p38α) or dominant-negative p38β (DN-p38β) MAPK expression was targeted to the heart. Compound transgenic DN-14-3-3/DN-p38β mice, and to a lesser extent compound transgenic DN-14-3-3/DN-p38α mice, exhibited reduced mortality and cardiac myocyte apoptosis in response to pressure overload, demonstrating that DN-14-3-3 promotes cardiac apoptosis due to stimulation of p38 MAPK activity.