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I-1-deficiency negatively impacts survival in a cardiomyopathy mouse model
Felix W Friedrich1,2, Hannieh Sotoud1,2, Birgit Geertz1,2
1Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Insights
Targeting beta-adrenergic receptor (AR) signaling via protein phosphatase-1 inhibitor-1 (I-1) ablation did not improve outcomes in a severe myosin-binding protein C (Mybpc3) related cardiomyopathy mouse model. Unexpectedly, double knockout mice showed reduced survival and worsened cardiac function.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) involves left ventricular hypertrophy, diastolic dysfunction, and fibrosis.
- Current treatments for HCM focus on beta-adrenergic receptor (AR) and calcium channel blockers.
- Protein phosphatase-1 inhibitor-1 (I-1) amplifies beta-AR signaling; I-1 deficient mice showed protection from pathological adrenergic stimulation.
Purpose of the Study:
- To investigate the therapeutic potential of I-1 ablation in a mouse model of severe myosin-binding protein C (Mybpc3)-related cardiomyopathy.
- To test the hypothesis that I-1 deficiency could improve outcomes in HCM by interfering with beta-AR signaling.
Main Methods:
- Mice deficient in I-1 were crossed with homozygous Mybpc3 knockout (KO) mice.
- Survival rates and cardiac function were assessed using longitudinal echocardiography.
- Key molecular markers, including PKA-downstream targets and hypertrophic markers, were analyzed.
Main Results:
- Double I-1/Mybpc3 KO mice exhibited shorter survival times compared to single Mybpc3 KO mice.
- Echocardiography revealed worsened cardiac function in double KO mice, including lower fractional area change and increased ventricular dimensions.
- Molecular analysis showed no significant differences in key signaling pathways or hypertrophic markers between single and double KO groups.
Conclusions:
- Interference with beta-AR signaling through I-1 ablation offers no long-term benefit in this severe Mybpc3-related cardiomyopathy model.
- The findings suggest that targeting this specific pathway may not be a viable therapeutic strategy for severe forms of this condition.
Aims:
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and increased interstitial fibrosis. Current treatment is based on beta-adrenoceptor (AR) and calcium channel blockers. Since mice deficient of protein phosphatase-1 inhibitor-1 (I-1), an amplifier in beta-AR signalling, were protected from pathological adrenergic stimulation in vivo, we hypothesized that I-1 ablation could result in an improved outcome in a HCM mouse model.
Methods And Results:
We crossed mice deficient of I-1 with homozygous myosin-binding protein C knock-out (Mybpc3 KO) mice exhibiting cardiac dilatation and reduced survival. Unexpectedly, survival time was shorter in double I-1/Mybpc3 KO than in single Mybpc3 KO mice. Longitudinal echocardiographic assessment revealed lower fractional area change, and higher diastolic left ventricular inner dimensions and end-diastolic volumes in Mybpc3 KO than in WT mice. In comparison to Mybpc3 KO, double I-1/Mybpc3 KO presented higher left ventricular end-diastolic volumes, inner dimensions and ventricular surface areas with increasing differences over time. Phosphorylation levels of PKA-downstream targets and mRNA levels of hypertrophic markers did not differ between I-1/Mybpc3 KO and single Mybpc3 KO mice, except a trend towards higher beta-myosin heavy chain levels in double I-1/Mybpc3 KO.
Conclusion:
The data indicate that interference with beta-AR signalling has no long-term benefit in this severe MYBPC3-related cardiomyopathy mouse model.
