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 (Ca(2+) ), 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 Ca(2+) homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca(2+) handling by pretreatment with β-blocker, carvedilol, or Ca(2+) -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.
Center for Clinical and Translational Sciences, Mayo Clinic, Rochester, Minnesota, USA.|Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
S P
SP
Wyles
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.|Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
S C
SC
Hrstka
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.|Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
S
S
Reyes
Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
A
A
Terzic
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.|Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
T M
TM
Olson
Center for Clinical and Translational Sciences, Mayo Clinic, Rochester, Minnesota, USA.|Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Transplant Center, Mayo Clinic, Rochester, Minnesota, USA.
T J
TJ
Nelson
D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology*; D000077261:Carvedilol; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological; D014700:Verapamil / Q000494:pharmacology
D002227:Carbazoles; D011412:Propanolamines; D016601:RNA-Binding Proteins; D011943:Receptors, Adrenergic, beta; C543725:ribonucleic acid binding motif protein 20, human; D000077261:Carvedilol; D014700:Verapamil; D002118:Calcium; D009638:Norepinephrine