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Published on: June 3, 2018
Hypoxic remodelling of Ca2+ stores does not alter human cardiac myofibroblast invasion
K Riches1, N T Hettiarachchi, K E Porter
1Leeds Institute for Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
Insights
Hypoxia increases intracellular calcium stores in cardiac myofibroblasts (CMFs) responding to bradykinin (BK). However, this calcium mobilization doesn't impact CMF proliferation or migration, suggesting calcium influx is key for these repair processes.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Myocardial Repair Mechanisms
Background:
- Cardiac fibroblasts transform into cardiac myofibroblasts (CMFs) for myocardial repair post-infarction.
- Cell proliferation and migration, crucial for repair, are calcium (Ca2+)-dependent processes.
- Hypoxia is a common condition post-myocardial infarction, affecting cellular function.
Purpose of the Study:
- To investigate the effect of hypoxia on bradykinin (BK)-induced calcium (Ca2+) signaling in human cardiac myofibroblasts (CMFs).
- To determine if hypoxia alters intracellular Ca2+ stores or capacitative Ca2+ entry (CCE) in CMFs.
- To assess the impact of hypoxia on BK-induced CMF proliferation and migration.
Main Methods:
- Primary human CMFs were cultured and subjected to normoxic or hypoxic conditions.
- Fura-2 microfluorimetry was used to measure intracellular Ca2+ mobilization and CCE.
- Cell proliferation and migration assays were performed under different oxygen levels.
Main Results:
- Hypoxia significantly increased Ca2+ mobilization from intracellular stores in response to BK.
- Hypoxia led to an increased CMF intracellular Ca2+-store content.
- Capacitative Ca2+ entry (CCE) remained unchanged under hypoxia.
- BK-induced CMF migration and proliferation were not affected by hypoxic exposure.
Conclusions:
- Hypoxia enhances BK-induced intracellular Ca2+ store mobilization in CMFs, but not capacitative Ca2+ entry.
- Ca2+ influx, rather than store mobilization, appears to be the primary driver of CMF migration and proliferation.
- These findings offer insights into CMF behavior in the hypoxic environment post-myocardial infarction.
Abstract:
Cardiac fibroblasts are the most abundant cell type in the heart, and play a key role in the maintenance and repair of the myocardium following damage such as myocardial infarction by transforming into a cardiac myofibroblast (CMF) phenotype. Repair occurs through controlled proliferation and migration, which are Ca(2+) dependent processes, and often requires the cells to operate within a hypoxic environment. Angiotensin converting enzyme (ACE) inhibitors reduce infarct size through the promotion of bradykinin (BK) stability. Although CMF express BK receptors, their activity under the reduced O(2) conditions that occur following infarct are entirely unexplored. Using Fura-2 microfluorimetry on primary human CMF, we found that hypoxia significantly increased the mobilisation of Ca(2+) from intracellular stores in response to BK whilst capacitative Ca(2+) entry (CCE) remained unchanged. The enhanced store mobilisation was due to a striking increase in CMF intracellular Ca(2+)-store content under hypoxic conditions. However, BK-induced CMF migration or proliferation was not affected following hypoxic exposure, suggesting that Ca(2+) influx rather than mobilisation is of primary importance in CMF migration and proliferation.
