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Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation
Talita M. Marin, … , Benjamin G. Neel, Maria I. Kontaridis
Talita M. Marin, … , Benjamin G. Neel, Maria I. Kontaridis
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1026-1043. https://doi.org/10.1172/JCI44972.
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Research Article Article has an altmetric score of 7

Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

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Abstract

LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.

Authors

Talita M. Marin, Kimberly Keith, Benjamin Davies, David A. Conner, Prajna Guha, Demetrios Kalaitzidis, Xue Wu, Jessica Lauriol, Bo Wang, Michael Bauer, Roderick Bronson, Kleber G. Franchini, Benjamin G. Neel, Maria I. Kontaridis

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Figure 12

Rapamycin normalizes HCM in LS/+ mice.

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Rapamycin normalizes HCM in LS/+ mice.
   
(A) H&E-stained longitudi...
(A) H&E-stained longitudinal sections of hearts from WT and LS/+ mice. Note normalization of hypertrophy in LS/+ hearts after rapamycin treatment (original magnification, ×100). (B) Reticulin stain of paraffin-embedded heart sections from 16-week-old WT and LS/+ mice (original magnification, ×400). (C) Quantification of average area (in μm2) of cardiomyocytes (200–500 cells counted/group) from WT or LS/+ cardiomyocytes isolated from mice that were either vehicle- or rapamycin-treated (2 mg/kg body weight) daily by i.p. injection for 4 weeks, then weekly for 4 weeks; see Results and Methods for details. Results are shown as the mean ± SEM. *P < 0.05, †P < 0.05. (D) Heart weight to body weight ratios of WT and LS/+ mice with vehicle- or rapamycin-treatment, as indicated. *P < 0.05, †P < 0.001. (E) Representative echocardiographs from 16-week-old vehicle-treated WT, vehicle-treated LS/+, or rapamycin-treated LS/+ mice. Two-headed arrows indicate left ventricle chamber size. (F) Anatomic and functional parameters of 12- and 16-week-old WT, LS/+, and LS/+ rapamycin-treated mice, as assessed by echocardiography, either after 4 weeks (measured at 12 weeks of age) or after 4 weeks of daily i.p. injections, followed by 4 weeks of weekly (measured at 16 weeks of age) i.p. injections. LVID-d, left ventricular chamber dimension in diastole. *P < 0.001 denotes significance between the vehicle-treated 16-week-old LS/+ mice and the LS/+ rapamycin-treated mice. All P values in C, D, and F were derived from ANOVA and Bonferroni post-test when ANOVA was significant.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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