Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes

Bradley D. Stewart, Caitlin E. Scott, Thomas P. McCoy, Guo Yin, Florin Despa, Sanda Despa, Peter M. Kekenes-Huskey

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca2+. These findings motivate our core hypothesis that non-selective inward Ca2+ conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca2+ load, which thereby magnifies intracellular Ca2+ transients. Questions remain however regarding the mechanism of amylin-induced Ca2+ dysregulation, including whether enhanced SL Ca2+ influx is sufficient to elevate cytosolic Ca2+ load [6], and if so, how might amplified Ca2+ transients perturb Ca2+-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca2+ signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca2+ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca2+ loading of the SR and that greater fractional release may contribute to the Ca2+-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca2+ in the SR and dyadic space collectively drive greater fractional SR Ca2+ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca2+ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca2+ dysregulation in pre-diabetes.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalCell Calcium
Volume71
DOIs
StatePublished - May 2018

Bibliographical note

Funding Information:
PKH dedicates this study to Anushka P. Michailova, who tragically passed away in the spring of 2014. Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under grant number P20GM103527 , NIH/NIGMS award R35GM124977 and NIH National Heart Lung and Blood Institute award R56HL131782 . This work was also supported by the National Institutes of Health ( R01HL118474 to FD and R01HL109501 to SD) and The National Science Foundation ( CBET 1357600 to FD).

Publisher Copyright:
© 2017 Elsevier Ltd

Keywords

  • Amylin Ca leak
  • Ca dysregulation
  • Ca transients
  • Cardiomyocytes
  • Pre-diabetic rats

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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