TY - JOUR
T1 - Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy
T2 - An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model
AU - Wyles, S. P.
AU - Hrstka, S. C.
AU - Reyes, S.
AU - Terzic, A.
AU - Olson, T. M.
AU - Nelson, T. J.
N1 - Publisher Copyright:
© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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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U2 - 10.1111/cts.12393
DO - 10.1111/cts.12393
M3 - Article
C2 - 27105042
AN - SCOPUS:84975060963
SN - 1752-8054
VL - 9
SP - 158
EP - 167
JO - Clinical and translational science
JF - Clinical and translational science
IS - 3
ER -