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Blocking cardiac growth in hypertrophic ... ecreased survival only in males
Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males.
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Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.
Luckey SW, Mansoori J, Fair K, Antos CL, Olson EN, Leinwand LA
American journal of physiology. Heart and circulatory physiology
2007-02-01 00:00
292
2
H838-45
Actins,Animals,Atrial Natriuretic Factor,Calcium-Binding Proteins,Cardiomyopathy, Hypertrophic,Crosses, Genetic,Dietary Proteins,Disease Models, Animal,Female,Fibrosis,Glycogen Synthase Kinase 3,Heart Ventricles,Kaplan-Meiers Estimate,Male,Mice,Mice, Inbred C57BL,Mice, Transgenic,Mutation,Myocardial Contraction,Myosin Heavy Chains,Phosphorylation,RNA, Messenger,Sarcoplasmic Reticulum Calcium-Transporting ATPases,Sex Factors,Time Factors,Ventricular Remodeling,Actins,Calcium-Binding Proteins,Dietary Proteins,Myosin Heavy Chains,RNA, Messenger,phospholamban,Atrial Natriuretic Factor,Glycogen Synthase Kinase 3,glycogen synthase kinase 3 beta,Sarcoplasmic Reticulum Calcium-Transporting ATPases
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Campus Box 347, Boulder, Colorado 80309-0347, USA
Am. J. Physiol. Heart Circ. Physiol.
NHLBI F32 HL-72565, NHLBI HL-56510
0363-6135
10.1152/ajpheart.00615.2006
00615.2006
683
True
17012357
