AKT-mTOR Signaling-Mediated Rescue of PRKAG2 R302Q Mutant-Induced Familial Hypertrophic Cardiomyopathy by Treatment with β-AR Blocker Metoprolol

2021 ◽  
Author(s):  
Jian Zhuo ◽  
Haihua Geng ◽  
Lihong Yao ◽  
Xiaohui Wu ◽  
Mengkang Fan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Therapeutic Strategy ◽  
Glycogen Storage ◽  
Mtor Signaling ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cellular Hypertrophy ◽  
Cardiac Syndrome ◽  
Mtor Phosphorylation ◽  
Ampk Activity ◽  
Glycogen Deposition

Abstract PRKAG2 cardiac syndrome, as a common form of metabolic hypertrophic cardiomyopathy (HCM) caused by mutations in PRKAG2 gene, often shows myocardial hypertrophy and abnormal glycogen deposition in cardiomyocytes. However, it remains incurable due to lacking of a management guideline for treatment. Herein, a β1-AR blocker Metoprolol was applied to 5 patients with PRKAG2 cardiac syndrome identified from a PRKAG2 R302Q mutant family, resulting in significantly postponed progression of cardiac hypertrophy. Overexpression of PRKAG2 R302Q in primary cardiomyocytes increased the activity of AMPK, induced cellular hypertrophy and glycogen storage, and promoted the phosphorylation levels of AKT-mTOR signaling. Application of either β1-AR blocker metoprolol or protein kinase A (PKA) inhibitor H89 to the cardiomyocytes rescued the HCM-like phenotypes induced by PRKAG2 R302Q, including suppression of both AKT-mTOR phosphorylation and AMPK activity. In conclusion, the current study not only determined the mechanism regulating HCM induced by PRKAG2 R302Q mutant, but also demonstrated a therapeutic strategy using β1-AR blocker to treat the patients with PRKAG2 cardiac syndrome.

Abstract 58: Modeling Pathogenesis in Familial Hypertrophic Cardiomyopathy Using Patient-Specific Induced Pluripotent Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Feng lan ◽  
Andrew Lee ◽  
Ping Liang ◽  
Enrique Navarrete ◽  
Li Wang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Molecular Genetic ◽  
Dermal Fibroblasts ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Patient Specific ◽  
Activated T Cells ◽  
Cellular Hypertrophy ◽  
Induced Pluripotent

Background: Hypertrophic cardiomyopathy (HCM) is a prevalent familial cardiac disorder linked to development of heart failure, arrhythmia, and sudden cardiac death. Molecular genetic studies have demonstrated HCM is caused by mutations in genes encoding for the cardiac sarcomere. However, the pathways by which sarcomeric mutations result in myocyte hypertrophy and contractile abnormalities are not well understood. Methods: We aimed to elucidate the molecular mechanisms underlying the development of HCM through the generation of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from dermal fibroblasts of a 10 member family, five of whom carry a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Results: As compared to control iPSC-CMs derived from healthy family members, HCM iPSC-CMs exhibited enlarged cell size, increased atrial natriuretic factor (ANF) expression, nuclear translocation of nuclear factor of activated T-cells (NFAT), and aggravated contractile dysfunction in response to stimulation by β-adrenergic agonists. Interestingly, both video analysis of beating cells and whole cell patch clamping revealed arrhythmia in a significant portion of diseased iPSC-CMs at the single cell level. Ca 2+ imaging demonstrated elevated cytoplasmic Ca 2+ content and irregular transients in HCM iPSC-CMs prior to the onset of cellular hypertrophy, suggesting the HCM phenotype is triggered by dysfunction in Ca 2+ cycling. Treatment of irregular Ca 2+ homeostasis by the Ca 2+ channel blocker verapamil prevented development of cellular hypertrophy and arrhythmia. Conclusions: We hypothesize the cellular abnormalities observed in HCM iPSC-CMs are caused by deficiencies in Ca 2+ regulation. We anticipate our findings will elucidate the mechanisms underlying HCM development and identify novel targets for treatment of the disease.

Abstract 243: A Novel PRKAG2 Mutation (K475E): Infantile-onset Hypertrophic Cardiomyopathy Phenotype and Impact on mTOR Signaling

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yanchun Xu ◽  
Hong Liu ◽  
Chanika Phornphutkul ◽  
D. Grahame Hardie ◽  
SC Dudley ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Transgenic Mice ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
H9c2 Cells ◽  
Mtor Signaling Pathway ◽  
Wild Type ◽  
Hek 293 ◽  
Cardiac Phenotype ◽  
Ampk Activity

Objective: PRKAG2 encodes the 2 subunit isoform of the 5’ AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload and hypertrophy. We identified a novel PRKAG2 mutation in a neonate with prenatal onset of HCM noted on a 27-week prenatal ultrasound. Molecular testing for HCM revealed a de novo PRKAG2 mutation (K475E). We aim to investigate the signaling pathway of mutation in PRKAG2 gene. Methods: HEK-293 and H9C2 cells stably expressing wild type (WT) or K475E FLAG-tagged 2 from a tetracycline-inducible promoter were established. Basal AMPK activities were measured at varying AMP concentrations. Phenformin-stimulated AMPK activity and T172-phosphorylation were also measured. Changes in mTOR signaling pathway were accessed by Western blot. Cells were treated with angiotensin II, rapamycin (RAPA) or both followed by staining or flow cytometry to assess cell area/size. Primary fibroblasts from the K475E patient and non-diseased controls were cultured and compared. Finally, transgenic mice with cardiac-specific overexpression of human wild type (Tg WT ) or K475E (TgK 475E ) were established for further study of the PRKAG2 phenotype by histology and echocardiography. Result: HEK-293 cells: K475E mutation induced a markedly increase in the basal AMPK activity and T172-phosphorylation, reduced sensitivity to AMP in allosteric activation and loss of response to phenformin. H9c2 cells: K475E mutation induced increases in the phosphorylation of p-P70S6K, p-4EBP1 and a hypertrophy phenotype which was reversed by RAPA. Transgenic mice: Tg K475E mice had an early onset hypertrophy and were prone to sudden death. Histology revealed large vacuoles and high glycogen content in Tg K475E myocytes throughout the ventricles. Echocardiography confirmed significantly enlarged heart in Tg K475E mice. Conclusions: We identified a novel infantile-onset PRKAG2 mutation with a severe cardiac phenotype. In vitro study revealed involvement of mTOR signaling pathway and reversal of the hypertrophy phenotype by mTOR inhibitor.

Role of Cardiac MRI in Detecting Familial Hypertrophic Cardiomyopathy: Review

2016 ◽  
Vol 1 (1) ◽  
pp. 4
Author(s):  
Marymol Koshy ◽  
Bushra Johari ◽  
Mohd Farhan Hamdan ◽  
Mohammad Hanafiah
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Magnetic Resonance ◽  
Genetic Disorder ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Non Invasive ◽  
Wide Range ◽  
Proper Diagnosis ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Use

Hypertrophic cardiomyopathy (HCM) is a global disease affecting people of various ethnic origins and both genders. HCM is a genetic disorder with a wide range of symptoms, including the catastrophic presentation of sudden cardiac death. Proper diagnosis and treatment of this disorder can relieve symptoms and prolong life. Non-invasive imaging is essential in diagnosing HCM. We present a review to deliberate the potential use of cardiac magnetic resonance (CMR) imaging in HCM assessment and also identify the risk factors entailed with risk stratification of HCM based on Magnetic Resonance Imaging (MRI).

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