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Intracellular Ca2+ Dysregulation in Coronary Smooth Muscle Is Similar in Coronary Disease of Humans and Ossabaw Miniature Swine

Abstract

Intracellular free Ca2+ ([Ca2+]i) dysregulation occurs in coronary smooth muscle (CSM) in atherosclerotic coronary artery disease (CAD) of metabolic syndrome (MetS) swine. Our goal was to determine how CAD severity, arterial structure, and MetS risk factors associate with [Ca2+]i dysregulation in human CAD compared to changes in Ossabaw miniature swine. CSM cells were dispersed from coronary arteries of explanted hearts from transplant recipients and from lean and MetS swine with CAD. CSM [Ca2+]i elicited by Ca2+ influx and sarcoplasmic reticulum (SR) Ca2+ release and sequestration was measured with fura-2. Increased [Ca2+]i signaling was associated with advanced age and a greater media area in human CAD. Decreased [Ca2+]i signaling was associated with a greater number of risk factors and a higher plaque burden in human and swine CAD. Similar [Ca2+]i dysregulation exhibited in human and Ossabaw swine CSM provides strong evidence for the translational relevance of this large animal model.

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Abbreviations

BMI:

Body mass index

[Ca2+]i :

Intracellular free calcium

CSM:

Coronary smooth muscle

CAD:

Coronary artery disease

LDL:

Low-density lipoprotein

LVAD:

Left ventricular assist device

MetS:

Metabolic syndrome

SERCA:

Sarco-endoplasmic reticulum Ca2+ ATPase

SR:

Sarcoplasmic reticulum

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Acknowledgements

The authors acknowledge the Indiana University School of Medicine Histology Core and Dr. Keith Condon for processing the histology and use of their equipment. Jill K. Badin’s Ph.D. thesis dated August 2019 contained some of the data in this manuscript and can be found at: https://scholarworks.iupui.edu/bitstream/handle/1805/20549/Badin_iupui_0104D_10379.pdf?isAllowed=y&sequence=1

Funding

This research was funded by the National Institutes of Health HL125385, P30 DK097512, the Joshua Diabetes Research Fund, and the Indiana University School of Medicine Center of Excellence in Cardiovascular Research.

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J.K.B., S.D.R., and M.S. are responsible for conception and design of research; J.K.B., C.E., S.D.R., M.A., Z.A.H., I.W., and J.P.G. performed experiments; J.K.B., C.E., and S.D.R. analyzed data; J.K.B., C.E., and M.S. interpreted results of experiments; J.K.B., C.E., and M.S. prepared figures; J.K.B. and C.E. drafted manuscript; J.K.B., C.E., and M.S. edited and revised manuscript; J.K.B., C.E., S.D.R., M.A., Z.A.H., I.W., J.P.G., and M.S. approved the final version of the manuscript.

Corresponding author

Correspondence to Michael Sturek.

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All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Institutional Animal Care and Use Committee at the Indiana University School of Medicine.

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This article does not contain any studies with human participants performed by any of the authors, as approved by exemption, per the use of discarded human tissue, by the Indiana University Institutional Review Board.

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Badin, J.K., Eggenberger, C., Rodenbeck, S.D. et al. Intracellular Ca2+ Dysregulation in Coronary Smooth Muscle Is Similar in Coronary Disease of Humans and Ossabaw Miniature Swine. J. of Cardiovasc. Trans. Res. (2021). https://doi.org/10.1007/s12265-021-10153-5

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Keywords

  • Atherosclerosis
  • Obesity
  • Metabolic syndrome
  • Histology
  • Sarco-endoplasmic reticulum Ca2+ ATPase
  • Ca2+ influx
  • Ca2+ release
  • Animal model
  • Risk factors