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EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy
Sila Algül1, Maike Schuldt1, Emmy Manders1,2
1Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (S.A., M.S., E.M., V.J., M.H., J.v.d.V., D.W.D.K.).
Insights
Researchers screened kinase inhibitors to find new ways to improve cardiac relaxation in hypertrophic cardiomyopathy (HCM). They identified EGFR/IGF1R signaling as a promising target for developing therapies to treat impaired relaxation in HCM patients.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Diastolic dysfunction is a key feature of heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM).
- Effective therapies to improve cardiac relaxation are limited due to an incomplete understanding of cardiomyocyte relaxation modulators.
- Kinase dysregulation is hypothesized to contribute to impaired relaxation in HCM.
Purpose of the Study:
- To identify novel modulators of cardiomyocyte relaxation through high-throughput screening of kinase inhibitors.
- To investigate kinase dysregulation in HCM patient myocardium.
- To validate potential therapeutic targets for impaired cardiac relaxation in HCM.
Main Methods:
- Screened 157 kinase inhibitors in isolated adult wild-type mouse cardiomyocytes to identify positive lusitropes (agents that improve relaxation).
- Performed phosphoproteomics and inferred kinase activity analysis on HCM patient myocardium.
- Validated identified kinase inhibitors in cardiomyocytes from a MYBPC3-mutation-induced HCM mouse model.
Main Results:
- Identified 21 novel positive lusitropes, clustering into cell cycle, EGFR/IGF1R, and Akt signaling pathways.
- HCM patient myocardium showed increased activation of EGFR/IGF1R pathway proteins.
- Three EGFR/IGF1R pathway inhibitors improved relaxation in HCM cardiomyocytes.
Conclusions:
- Demonstrated the feasibility of screening for cardiomyocyte relaxation modulators.
- Kinases in EGFR/IGF1R, Akt, cell cycle, and FoxO signaling pathways modulate cardiomyocyte relaxation and contraction.
- Inhibition of EGFR/IGF1R signaling represents a promising therapeutic strategy for impaired relaxation in HCM.
Background:
Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM.
Methods:
We optimized and increased the throughput of unloaded shortening measurements and screened a kinase inhibitor library in isolated adult cardiomyocytes from wild-type mice. One hundred fifty-seven kinase inhibitors were screened. To assess which kinases are dysregulated in patients with HCM and could contribute to impaired relaxation, we performed a tyrosine and global phosphoproteomics screen and integrative inferred kinase activity analysis using HCM patient myocardium. Identified hits from these 2 data sets were validated in cardiomyocytes from a homozygous MYBPC3c.2373insG HCM mouse model.
Results:
Screening of 157 kinase inhibitors in wild-type (N=33) cardiomyocytes (n=24 563) resulted in the identification of 17 positive inotropes and 21 positive lusitropes, almost all of them novel. The positive lusitropes formed 3 clusters: cell cycle, EGFR (epidermal growth factor receptor)/IGF1R (insulin-like growth factor 1 receptor), and a small Akt (α-serine/threonine protein kinase) signaling cluster. By performing phosphoproteomic profiling of HCM patient myocardium (N=24 HCM and N=8 donors), we demonstrated increased activation of 6 of 8 proteins from the EGFR/IGFR1 cluster in HCM. We validated compounds from this cluster in mouse HCM (N=12) cardiomyocytes (n=2023). Three compounds from this cluster were able to improve relaxation in HCM cardiomyocytes.
Conclusions:
We showed the feasibility of screening for functional modulators of cardiomyocyte relaxation and contraction, parameters that we observed to be modulated by kinases involved in EGFR/IGF1R, Akt, cell cycle signaling, and FoxO (forkhead box class O) signaling, respectively. Integrating the screening data with phosphoproteomics analysis in HCM patient tissue indicated that inhibition of EGFR/IGF1R signaling is a promising target for treating impaired relaxation in HCM.
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