Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice

Genomics. 2008 Jan;91(1):52-60. doi: 10.1016/j.ygeno.2007.09.005. Epub 2007 Dec 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cardiomyopathy, Hypertrophic, Familial / genetics
  • Cardiomyopathy, Hypertrophic, Familial / metabolism*
  • Cardiomyopathy, Hypertrophic, Familial / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Chromosome Disorders / genetics
  • Chromosome Disorders / metabolism*
  • Chromosome Disorders / pathology
  • Extracellular Signal-Regulated MAP Kinases
  • Gene Expression Profiling
  • Gene Expression Regulation* / genetics
  • Heterozygote
  • Homozygote
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism*
  • Hypertrophy, Left Ventricular / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Oligonucleotide Array Sequence Analysis
  • Ventricular Septum / metabolism
  • Ventricular Septum / pathology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Carrier Proteins
  • myosin-binding protein C
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4