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 4

Low-dose dasatinib treatment rescues cardiac dysfunction of NS mice.

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Low-dose dasatinib treatment rescues cardiac dysfunction of NS mice. (A)...
(A) Schematic representation of postdevelopmental dasatinib treatment. WT and NS mice (D61G/+) were treated daily with vehicle or 0.1 mg/kg dasatinib (i.p.) from P10 to P42 and then treatment was discontinued for 2 weeks. Echocardiography (E), invasive hemodynamic measurement (H), and surgery (S) were performed at the indicated time points (P42 and P56). (B) Representative echocardiographic images of vehicle- or dasatinib-treated WT and NS mice at P42. Ejection fraction (EF) percentage was measured from echocardiograms (n = 7 for vehicle-treated WT mice; n = 6 for vehicle-treated NS mice and dasatinib-treated WT and NS mice). (C) Representative echocardiographic images of vehicle- or dasatinib-treated WT and NS mice at P56. EF percentage was measured from echocardiograms (n = 9 for vehicle-treated WT and NS mice, n = 6 for dasatinib-treated WT and NS mice). (D) Left ventricle blood pressure (LV pressure) and the maximum rate of pressure change in the left ventricle (dP/dtmax) were measured in vehicle- and dasatinib-treated WT and NS mice by invasive hemodynamics (n = 8 for WT mouse groups, n = 9 for NS mouse groups). Data represent the mean ± SEM and were analyzed by 2-way ANOVA and Tukey’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001.