Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes

Research output: Contribution to journalArticle

Authors

  • Sen Li
  • Anant Chopra
  • Wendy Keung
  • Camie W.Y. Chan
  • Kevin D. Costa
  • Chi Wing Kong
  • Roger J. Hajjar
  • Christopher S. Chen
  • Ronald A. Li

External Institution(s)

  • The University of Hong Kong
  • Icahn School of Medicine at Mount Sinai
  • Boston University
  • Harvard University
  • Karolinska Institutet

Details

Original languageEnglish (US)
Pages (from-to)H1105-H1115
JournalAmerican journal of physiology. Heart and circulatory physiology
Volume317
Issue number5
StatusPublished - Nov 1 2019
Peer-reviewedYes

Abstract

Human pluripotent stem cell (hPSCs)-derived ventricular (V) cardiomyocytes (CMs) display immature Ca2+-handing properties with smaller transient amplitudes and slower kinetics due to such differences in crucial Ca2+-handling proteins as the poor sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump but robust Na+-Ca2+ exchanger (NCX) activities in human embryonic stem cell (ESC)-derived VCMs compared with adult. Despite their fundamental importance in excitation-contraction coupling, the relative contribution of SERCA and NCX to Ca2+-handling of hPSC-VCMs remains unexplored. We systematically altered the activities of SERCA and NCX in human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs) and their engineered microtissues, followed by examining the resultant phenotypic consequences. SERCA overexpression in hESC-VCMs shortened the decay of Ca2+ transient at low frequencies (0.5 Hz) without affecting the amplitude, SR Ca2+ content and Ca2+ baseline. Interestingly, short hairpin RNA-based NCX suppression did not prolong the transient decay, indicating a compensatory response for Ca2+ removal. Although hESC-VCMs and their derived microtissues exhibited negative frequency-transient/force responses, SERCA overexpression rendered them less negative at high frequencies (>2 Hz) by accelerating Ca2+ sequestration. We conclude that for hESC-VCMs and their microtissues, SERCA, rather than NCX, is the main Ca2+ remover during diastole; poor SERCA expression is the leading cause for immature negative-frequency/force responses, which can be partially reverted by forced expression. Combinatorial approach to mature calcium handling in hESC-VCMs may help shed further mechanistic insights.NEW & NOTEWORTHY In this study of human pluripotent stem cell-derived cardiomyocytes, we studied the role of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and Na+-Ca2+ exchanger (NCX) in Ca2+ handling. Our data support the notion that SERCA is more effective in cytosolic calcium removal than the NCX.

    Research areas

  • SERCA pump, engineered cardiac tissue, pluripotent stem cell-derived cardiomyocytes, sodium/calcium exchanger

Citation formats

APA

Li, S., Chopra, A., Keung, W., Chan, C. W. Y., Costa, K. D., Kong, C. W., ... Li, R. A. (2019). Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes. American journal of physiology. Heart and circulatory physiology, 317(5), H1105-H1115. https://doi.org/10.1152/ajpheart.00540.2018

Harvard

Li, S, Chopra, A, Keung, W, Chan, CWY, Costa, KD, Kong, CW, Hajjar, RJ, Chen, CS & Li, RA 2019, 'Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes', American journal of physiology. Heart and circulatory physiology, vol. 317, no. 5, pp. H1105-H1115. https://doi.org/10.1152/ajpheart.00540.2018