Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice.
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by left ventricular hypertrophy (LVH) predominantly affecting the interventricular septum. Cardiac myosin-binding protein C (cMyBP-C) mutations are common causes of FHC. Gene expression profiling was performed in left ventricles of 9-week-old wild-type mice, heterozygous cMyBP-C KO mice displaying asymmetric septal hypertrophy, and homozygous mice developing eccentric LVH. Knocking out one or two cMyBP-C genes leads primarily to gene expression changes indicating an increased energy demand, activation of the JNK and p38 parts of the MAPK pathway and deactivation of the ERK part, and induction of apoptosis. Altered gene expression for processes related to cardiac structure, contractile proteins, and protein turnover was also identified. Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice.
Department of Genetics and Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
L M T
LM
Eijssen
B J C
BJ
van den Bosch
N
N
Vignier
P J
PJ
Lindsey
C M M
CM
van den Burg
L
L
Carrier
P A
PA
Doevendans
G J
GJ
van der Vusse
H J M
HJ
Smeets
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D054088:Ventricular Septum / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D048051:p38 Mitogen-Activated Protein Kinases; D000099163:Myosin Binding Protein C