Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model

S. P. Wyles, S. C. Hrstka, S. Reyes, Andre Terzic, Timothy Mark Olson, Timothy J Nelson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca2+), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca2+ homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca2+ handling by pretreatment with β-blocker, carvedilol, or Ca2+-channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic loci in familial DCM hiPSC-CMs after β-adrenergic stimulation. These translational data provide patient-based in vitro analysis of β-adrenergic stress in RBM20-deficient familial DCM hiPSC-CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized, but more importantly generalized in the clinic.

Original languageEnglish (US)
Pages (from-to)158-167
Number of pages10
JournalClinical and Translational Science
Volume9
Issue number3
DOIs
StatePublished - Jun 1 2016

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Induced Pluripotent Stem Cells
Stem cells
Cardiac Myocytes
Adrenergic Agents
Homeostasis
Modulation
Pharmacology
Calcium
DNA Nucleotidylexotransferase
Dilated Cardiomyopathy
Verapamil
Cardiomyopathies
Labeling
Area Under Curve
Disease Progression
Heart Diseases
Mutation
In Vitro Techniques
Familial dilated cardiomyopathy
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model",
abstract = "For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca2+), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca2+ homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca2+ handling by pretreatment with β-blocker, carvedilol, or Ca2+-channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic loci in familial DCM hiPSC-CMs after β-adrenergic stimulation. These translational data provide patient-based in vitro analysis of β-adrenergic stress in RBM20-deficient familial DCM hiPSC-CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized, but more importantly generalized in the clinic.",
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AU - Nelson, Timothy J

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