Abstract 5292: Adrenergic Stress Unmasks Exaggerated Septal Hypertrophy and Proteasome Impairment in Heterozygous cMyBP-C Mutant Mice
Familial hypertrophic cardiomyopathy (FHC) is characterized by asymmetric septal hypertrophy and often associated with mutations in the cardiac myosin-binding protein C (cMyBP-C) gene. In contrast to humans, in which hypertrophy already exists at the heterozygous state, mouse models of FHC develop hypertrophy mainly at the homozygous state. A major reason for this discrepancy may be the unphysiological “sedentary” lifestyle of caged mice. To test this hypothesis, we subjected two targeted heterozygous cMyBP-C mice to adrenergic stress. The first model carries a G>A transition on the last nucleotide of exon 6 (KI), and expresses wild-type (WT) as well as mutant cMyBP-C. The other one is a knock-out (KO), which does not express any cMyBP-C. Mice (5 months, n=7–8) were treated with isoprenaline/phenylephrine (Iso/PE; both 15 mg/Kg/d) or NaCl via osmotic minipump for 1 week. Cardiac phenotype was evaluated by high resolution echo and compared to WT. Under basal conditions KI and KO had normal ventricular weight. Iso/PE induced hypertrophy in all groups, but to a greater extent in KI and KO (+35% and +53%, respectively vs. +28% in WT). The increase in posterior wall thickness was similar in all groups, but the increase in septum was 8-fold higher in KI/KO vs. WT. To evaluate whether the ubiquitin-proteasome system (UPS) was altered in Iso/PE-induced hypertrophy, chymotrypsin-like activity of the proteasome was determined. Whereas the activity was similar in KO and WT under all conditions, it was 40% lower after Iso/PE (p<0.001) and negatively correlated with ventricular weight in KI (r=−0.74, p<0.01). These data showed that
adrenergic stress unmasks a FHC phenotype in both heterozygous cMyBP-C KI and KO mice and
revealed UPS impairment only in KI mice, which express mutant cMyBP-C.
The latter exactly mirrors the genetic situation in affected FHC patients, suggesting that UPS impairment could contribute to the pathophysiology of FHC associated with cMyBP-C gene mutations.