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

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 hum...

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Bibliographic Details
Published in:	Clinical and translational science Vol. 9; no. 3; pp. 158 - 167
Main Authors:	Wyles, SP, Hrstka, SC, Reyes, S, Terzic, A, Olson, TM, Nelson, TJ
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-06-2016 John Wiley and Sons Inc
Subjects:	Apoptosis Apoptosis - drug effects Calcium Calcium (intracellular) Calcium - metabolism Calcium homeostasis Calcium ions Calcium Signaling - drug effects Carbazoles - pharmacology Cardiomyocytes Cardiomyopathy Cardiomyopathy, Dilated - metabolism Cardiomyopathy, Dilated - pathology Cardiovascular disease Cardiovascular diseases Coronary artery disease Dilated cardiomyopathy DNA nucleotidylexotransferase Drug testing Heart diseases Heart failure Homeostasis Homeostasis - drug effects Humans Hypotheses Induced Pluripotent Stem Cells - metabolism Models, Biological Mutation Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Norepinephrine - pharmacology Pluripotency Pretreatment Propanolamines - pharmacology Proteins Receptors, Adrenergic, beta - metabolism RNA-Binding Proteins - metabolism Sarcomeres - drug effects Sarcomeres - metabolism Stem cells Stimulation Stress response Stress, Physiological Studies Therapeutic applications Verapamil Verapamil - pharmacology United States > US Minnesota
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1752-8054 1752-8062
DOI:	10.1111/cts.12393