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K475E PRKAG2 Mutation: Cardiac Phenotype and Targeted Therapy Using Rapamycin
Author(s) -
Tseng YiTang,
Wang Zhengke,
Padbury James,
Phornphutkul Chanika
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb479
Subject(s) - glycogen , medicine , muscle hypertrophy , hypertrophic cardiomyopathy , endocrinology , genetically modified mouse , diabetic cardiomyopathy , ventricular hypertrophy , cardiomyopathy , cardiac function curve , phenotype , transgene , pi3k/akt/mtor pathway , biology , left ventricular hypertrophy , heart failure , apoptosis , biochemistry , blood pressure , gene
Background We identified a novel mutation (K475E) in PRKAG2 , coding for protein kinase AMP‐activated non‐catalytic subunit γ2, during a 27‐week prenatal ultrasound. A hypertrophic cardiomyopathy (HCM) phenotype was later confirmed. We have demonstrated in vitro that the K475E mutation led to increases in cardiomyocytes size and area which can be reversed by rapamycin. We have developed transgenic mouse lines with cardiac‐specific expression of the human wild type (Tg WT ) or K475E mutant (Tg K475E ) PRKAG2 . The Tg K475E mice exhibit many human PRKAG2 HCM phenotypes, including cardiac hypertrophy, glycogen overload and sudden death. Objective To characterize K475E‐induced cardiac phenotype in vivo and develop a targeted therapy using mTOR inhibition strategy for PRKAG2 mutation‐induced HCM. Methods Cardiac hypertrophy was monitored and cardiac glycogen levels were measured at several developmental stages. Neonatal mice (2‐wk old) were treated daily with vehicle or rapamycin (2 mg/kg, ip) for 4 weeks. Cardiac function was monitored longitudinally by echocardiography. Results Hypertrophy in Tg K475E mice was confirmed. Histology revealed large vacuoles and high glycogen content in Tg K475E myocytes throughout the ventricles. Echocardiography confirmed that LV mass dramatically increased in Tg K475E mice starting from 5 weeks of age. Daily rapamycin treatment for 2 weeks dramatically decreased 1) cardiac hypertrophy and 2) glycogen overload in Tg K475E mice. These beneficial effects of rapamycin were significantly tempered, however, when we switched to an alternative dosing regimen (one ip injection/3 days) of rapamycin. Conclusion The new transgenic mouse model reflects the early onset phenotype of the K475E mutation‐induced HCM in humans. The mTOR signaling pathway is involved in K475E induced HCM. Moreover, the mTOR inhibition strategy as targeted therapy for PRKAG2 induced HCM is effective and should be studied further. Support or Funding Information This study was supported by NIH P30GM114750 and the Oh‐Zopfi Research Award, Women & Infant's Hospital. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .