Hypoxic remodelling of Ca2+ stores does not alter human cardiac myofibroblast invasion

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 Ca2+ 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 O2 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 Ca2+ from intracellular stores in response to BK whilst capacitative Ca2+ entry (CCE) remained unchanged. The enhanced store mobilisation was due to a striking increase in CMF intracellular Ca2+-store content under hypoxic conditions. However, BK-induced CMF migration or proliferation was not affected following hypoxic exposure, suggesting that Ca2+ influx rather than mobilisation is of primary importance in CMF migration and proliferation.

Research highlights
► Bradykinin promotes migration and proliferation of myofibroblasts.
► Such activity is Ca2+-dependent and occurs under hypoxic conditions.
► Hypoxia increased myofibroblast Ca2+ stores but not influx evoked by bradykinin.
► Myofibroblast migration and proliferation was unaffected by hypoxia.