Low-dose dasatinib rescues cardiac function in Noonan syndrome
Jae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, Anton M. Bennett
Jae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, Anton M. Bennett
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Research Article Cardiology Therapeutics

Low-dose dasatinib rescues cardiac function in Noonan syndrome

Abstract

Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies.

Authors

Jae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, Anton M. Bennett

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Figure 7

Low-dose dasatinib prevents cardiac fibrosis in Ptpn11-associated NS and NSML mice.

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Low-dose dasatinib prevents cardiac fibrosis in Ptpn11-associated NS and...
(A) Masson’s trichrome and Picrosirius red stains of left ventricles from postnatal vehicle- and dasatinib-treated WT and NS mice (D61G/+) at P56 (scale bar: 50 μm). (B) Total heart RNA was isolated from postnatal vehicle- and dasatinib-treated WT and NS mice. Col1a2 and Col3a1 were measured by quantitative RT-PCR and normalized to the vehicle-treated WT group (n = 6 per group). (C) Masson’s trichrome and Picrosirius red stains of left ventricles from postnatal vehicle- or dasatinib-treated WT and NSML mice (Y279C/+) at P56 (scale bar: 50 μm). (D) Total heart RNA was isolated from postnatal vehicle- and dasatinib-treated WT and NSML mice. Col1a2 and Col3a1 were measured by quantitative RT-PCR and normalized to the vehicle-treated WT group (n = 6 per group). Data represent mean ± SEM and were analyzed by 2-way ANOVA and Tukey’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001.