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Reversible alteration of calcium dynamics in cardiomyocytes during acute hypoxia transient in a microfluidic platform
S Martewicz1, F Michielin, E Serena
1Dipartimento di Principi e Impianti di Ingegneria Chimica, University of Padova, Via Marzolo, 9, 35131 Padova, Italy.
Insights
Investigating early hypoxic events in heart cells, this study reveals reversible changes in intracellular calcium dynamics. These alterations, linked to L-type calcium channels, may offer cardioprotection during ischemia.
Area of Science:
- Cardiology
- Cellular Physiology
- Biomedical Engineering
Background:
- Heart disease is a major cause of death, with ischemia frequently leading to myocardial damage.
- Ischemia-induced hypoxia disrupts cardiomyocyte function, particularly calcium handling, impacting cell survival.
- Altered calcium dynamics are implicated in both acute and chronic ischemic heart conditions, including arrhythmias and heart failure.
Purpose of the Study:
- To investigate intracellular calcium dynamics in cardiomyocytes during the initial phase of hypoxia.
- To understand the functional consequences of rapid oxygen level changes on cardiac cells.
- To explore potential adaptive mechanisms for cardiopreservation.
Main Methods:
- Development of a microfluidic system for controlled, rapid oxygen concentration changes.
- In-line analysis of intracellular calcium concentration using confocal microscopy.
- Utilizing Fluo-4 loaded neonatal rat cardiomyocytes for experiments.
Main Results:
- Hypoxia induced reversible changes in intracellular calcium (Ca2+) transients in cardiomyocytes.
- These effects were observed at oxygen partial pressures below 5%.
- Calcium channel antagonist mimicked hypoxia-induced Ca2+ dynamic alterations, implicating L-type calcium channels.
Conclusions:
- Early hypoxic events trigger reversible alterations in cardiomyocyte calcium dynamics.
- Changes in L-type calcium channel function appear to be involved in the response to low oxygen.
- These reversible functional changes may serve as an adaptive cardioprotective mechanism during ischemia.
Abstract:
Heart disease is the leading cause of mortality in western countries. Apart from congenital and anatomical alterations, ischemia is the most common agent causing myocardial damage. During ischemia, a sudden decrease in oxygen concentration alters cardiomyocyte function and compromises cell survival. The calcium handling machinery, which regulates the main functional features of a cardiomyocyte, is heavily compromised during acute hypoxic events. Alterations in calcium dynamics have been linked to both short- and long-term consequences of ischemia, ranging from arrhythmias to heart failure. In this perspective, we aimed at investigating the calcium dynamics in functional cardiomyocytes during the early phase of a hypoxic event. For this purpose, we developed a microfluidic system specifically designed for controlling fast oxygen concentration dynamics through a gas micro-exchanger allowing in line analysis of intracellular calcium concentration by confocal microscopy. Experimental results show that exposure of Fluo-4 loaded neonatal rat cardiomyocytes to hypoxic conditions induced changes in intracellular Ca(2+) transients. Such behavior was reversible and was detected for hypoxic levels below 5% of oxygen partial pressure. The observed changes in Ca(2+) dynamics were mimicked using specific L-type Ca(2+) channel antagonists, suggesting that alterations in calcium channel function occur at low oxygen levels. Reversible alteration in ion channel function, that takes place in response to changes in cellular oxygen, might represent an adaptive mechanism of cardiopreservation during ischemia.
