Identification of cardiomyocytes' characteristics responsible for dynamical changes in calcium profile in response to mechano-chemo transduction

Abstract

Background: We embedded cardiomyocytes in a cross-linked hydrogel to study the effect of increased afterload on in the heart. We observed that mechanically-loaded cardiomyocytes undergo noticeable changes in their Ca2+ dynamics that can compensate for the increase in load. We have shown that these changes are mediated by the upregulation of nitric oxide (NO) signaling, which in turns affects Ca2+ handling. Because many different Ca2+ pathways could be affected we used an agnostic approach based on mathematical modeling to tease out changes in cell characteristics responsible for the difference in calcium and contraction profiles between load-free and after-load environments. Mathematical Method: We use a mathematical model to simulate the extracellular environment, and use the simulation results coupled with the experimental observations to identify parameters that change between load-free and after-load conditions. The mathematical model details a closed feedback loop between the calcium system and the extracellular environment to give rise to the self-regulation we observed. We ran extensive simulations where parameters associated with the influx and efflux of calcium are modulated such that they are either up-regulated or down-regulated by NO. In silico results are filtered out to qualitatively match cell-in-gel in vivo results. The filtering process is based on measures that capture multiple properties of calcium profiles. Conclusion: Our agnostic approach of identification hints that upregulation of NO modulates multiple parameters of the Ca2+ handling pathways simultaneously. Of the modulated parameters, the L-type current amplitude has to be consistently increased. Coupled with the increase in L-type current, cell’s parameters associated with release of calcium from the SR and uptakes of calcium by the SR have to be modulated in opposite directions.