doi: 10.1161/hc0302.102593
(Circulation. 2002;105:380.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Bone Marrow–Derived Regenerated Cardiomyocytes (CMG Cells) Express Functional Adrenergic and Muscarinic Receptors
From the Cardiopulmonary Division (D.H., K.F., S.M., F.K., Y.T., T.M., Y.S., S.O.), Department of Internal Medicine, Institute for Advanced Cardiac Therapeutics (K.F.), and the Department of Pathology (A.U.), Keio University School of Medicine, Tokyo, Japan.
Correspondence to Keiichi Fukuda, MD, PhD, Institute for Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail:kfukuda{at}sc.itc.keio.ac.jp
Background— We recently reported that cardiomyocytes could be differentiated from bone marrow mesenchymal stem cells in vitro by 5-azacytidine treatment. In native cardiomyocytes, adrenergic and muscarinic receptors play crucial roles in mediating heart rate, conduction velocity, contractility, and cardiac hypertrophy. We investigated whether these receptors are expressed in differentiated CMG cells, and if so, whether they have downstream signaling systems.
Methods and Results— Reverse transcription–polymerase chain reaction revealed that CMG cells had already expressed 
1A-, 1B-, and 1D-adrenergic receptor mRNA before 5-azacytidine treatment, whereas expression of ß1-, ß2-adrenergic and M1-, M2-muscarinic receptors was first detected at 1 day. Phenylephrine dose-dependently induced phosphorylation of ERK1/2, which was completely inhibited by prazosin, and significantly increased cell size. Isoproterenol augmented cAMP by 38-fold, which was fully inhibited by propranolol. Isoproterenol (10-7 mol/L) increased the spontaneous beating rate by 47.6% (basal, 127±16 bpm), and propranolol and CGP20712A (ß1-selective blocker) reduced it by 79.0% and 71.0%, respectively, whereas ICI118551 (ß2-selective blocker) induced slight reduction. Cell motion, percent shortening, and contractile velocity were increased by 37.5%, 26.9%, and 50.6%, respectively, in response to isoproterenol. Phenylephrine and isoproterenol augmented ANP and BNP gene expressions. Carbachol increased IP3 by 32-fold, which was markedly inhibited by atropine as well as AFDX116 (M2-selective blocker) measured by radioimmunoassay.
Conclusions— These findings indicate that CMG cells expressed 1A, 1B, and 1D receptors before differentiation and expressed ß1, ß2, M1, and M2 receptors after they obtained the cardiomyocyte phenotype. These receptors had functional signal transduction pathways and could modulate cell function.
Key Words: cells • heart rate • receptors, adrenergic, beta • signal transduction • receptors, adrenergic, alpha
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