Calcium Transients Closely Reflect Prolonged Action Potentials in iPSC Models of Inherited Cardiac Arrhythmia
| Autor: | Craig T. January, Kevin E. Healy, Jianhua Zhang, Ethan A. Hua, Marie A.F. Sears, Jonathan C. Makielski, Julianne Wojciak, Melvin M. Scheinman, Paweena Lizarraga, Chi-cheng Fu, Kenta Nakamura, Sadguna Y. Balijepalli, Yohei Hayashi, Shiro Baba, Shinya Yamanaka, C. Ian Spencer, Kiichiro Tomoda, Timothy J. Kamp, Bruce R. Conklin, Katriina Aalto-Setälä |
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| Rok vydání: | 2014 |
| Předmět: |
Patch-Clamp Techniques
Action Potentials 030204 cardiovascular system & hematology Arrhythmias Cardiovascular Biochemistry Calcium in biology NAV1.5 Voltage-Gated Sodium Channel chemistry.chemical_compound 0302 clinical medicine Myocyte 2.1 Biological and endogenous factors Myocytes Cardiac lcsh:QH301-705.5 lcsh:R5-920 0303 health sciences Stem Cell Research - Induced Pluripotent Stem Cell - Human Cardiac action potential Cell Differentiation Single Nucleotide Middle Aged 3. Good health Phenotype Heart Disease Tetrodotoxin Female lcsh:Medicine (General) Cardiac medicine.drug medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Nifedipine Genotype Induced Pluripotent Stem Cells Clinical Sciences chemistry.chemical_element Biology Calcium Polymorphism Single Nucleotide Sudden death Article 03 medical and health sciences Young Adult Internal medicine Caffeine medicine Genetics Humans cardiovascular diseases Polymorphism 030304 developmental biology Myocytes Stem Cell Research - Induced Pluripotent Stem Cell Infant Newborn Cardiac arrhythmia Infant Arrhythmias Cardiac Cell Biology Newborn Stem Cell Research Ether-A-Go-Go Potassium Channels Endocrinology lcsh:Biology (General) chemistry Biochemistry and Cell Biology Developmental Biology |
| Zdroj: | Stem cell reports, vol 3, iss 2 Stem Cell Reports Stem Cell Reports, Vol 3, Iss 2, Pp 269-281 (2014) Spencer, CI; Baba, S; Nakamura, K; Hua, EA; Sears, MAF; Fu, CC; et al.(2014). Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports, 3(2), 269-281. doi: 10.1016/j.stemcr.2014.06.003. UCSF: Retrieved from: http://www.escholarship.org/uc/item/9720z7s2 |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2014.06.003 |
| Popis: | Summary Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca2+]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca2+]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca2+. Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca2+]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na+-Ca2+ exchange. These results suggest that LQTS mutations act partly on cytosolic Ca2+ cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site. Highlights • The long-QT syndrome is a malignant cause of human inherited cardiac arrhythmias • Heart cells reprogrammed from two types of LQTS had very prolonged contractions • Long-QT cardiomyocytes were controlled by drugs affecting calcium transients • Drugs targeting calcium transients might remedy multiple types of LQTS The differentiation of patient-derived induced pluripotent stem cells (iPSCs) into cardiomyocytes provides unprecedented opportunities for investigating inherited cardiac arrhythmia syndromes in native tissue. Here, Conklin and colleagues used cardiomyocytes derived from patients carrying dissimilar variants of long-QT syndrome to reveal a common arrhythmogenic cellular pathway. The findings support functionally targeted therapy that is independent of the specific causal mutations. |
| Databáze: | OpenAIRE |
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