Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells |
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| Institution: | 1. Cardiac Signaling Center of MUSC, USC and Clemson, Charleston, SC, USA;2. Department of Pharmacology,Georgetown University Medical Center, Washington, DC, USA;1. Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110001, China;2. Cardiovascular Institute of China Medical University, Shenyang 110001, China;3. Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan;4. Respiratory Department and Intensive Care Unit, Shengjing Hospital of China Medical University, Shenyang 110004, China;1. Stanford Cardiovascular Institute, Stanford, CA 94305-5454, USA;2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA 94305, USA;3. Departments of Medicine and Pharmacology, University of California, San Diego, CA 92093, USA;4. Institute of Pharmacology and Toxicology, University Medical Center Goettingen, 37075 Goettingen, Germany;5. DZHK (German Center for Cardiovascular Research), Partner Site, Goettingen, Germany;6. Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA;1. iBB - Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal;2. The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal;3. Centro de Química-Física Molecular and Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal |
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| Abstract: | AimsThe effects of acute (100 s) hypoxia and/or acidosis on Ca2+ signaling parameters of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are explored here for the first time.Methods and results1) hiPSC-CMs express two cell populations: rapidly-inactivating ICa myocytes (τi<40 ms, in 4–5 day cultures) and slowly-inactivating ICa (τi ≥ 40 ms, in 6–8 day cultures). 2) Hypoxia suppressed ICa by 10–20% in rapidly- and 40–55% in slowly-inactivating ICa cells. 3) Isoproterenol enhanced ICa in hiPSC-CMs, but either enhanced or did not alter the hypoxic suppression. 4) Hypoxia had no differential suppressive effects in the two cell-types when Ba2+ was the charge carrier through the calcium channels, implicating Ca2+-dependent inactivation in O2 sensing. 5) Acidosis suppressed ICa by ∼35% and ∼25% in rapidly and slowly inactivating ICa cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was ∼25% in global and ∼37% in RyR2 Ca2+-microdomains in either cell type, whereas with hypoxia suppression was ∼20% and ∼25% respectively in global and RyR2-microdomaine in rapidly and ∼35% and ∼45% respectively in global and RyR2-microdomaine in slowly-inactivating cells.ConclusionsVariability in ICa inactivation kinetics rather than cellular ancestry seems to underlie the action potential morphology differences generally attributed to mixed atrial and ventricular cell populations in hiPSC-CMs cultures. The differential hypoxic regulation of Ca2+-signaling in the two-cell types arises from differential Ca2+-dependent inactivation of the Ca2+-channel caused by proximity of Ca2+-release stores to the Ca2+ channels. |
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| Keywords: | L-type Ca(2+) channel Hypoxia Acidosis Ischemia Human induced pluripotent stem cells derived cardiomyocytes |
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