Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Abstract

Our studies suggest that acute hypoxia suppresses I in rapidly inactivating cell population by a mechanism involving Ca-dependent inactivation, while compromised mitochondrial Ca uptake seems also to contribute to I suppression in slowly inactivating cell population. Proximity of cellular Ca pools to sarcolemmal Ca channels may contribute to the variability of inactivation kinetics of I in the two cell populations, while acidosis suppression of I appears mediated by proton-induced block of the calcium channel.

Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells

“…While the suppressive effects of hypoxia on I Ca depended critically on the cell type expressing slowly or rapidly inactivating Ca 2+ channels, acidosis effects were independent of cell types. The stronger suppressive effects of hypoxia on slowly inactivating I Ca cells was consistent with the idea that Ca 2+ dependent inactivation protects the channel against hypoxic suppression (scheme 1), somewhat similar to that found in adult and neonatal rat cardiomyocytes where suppression of CDI by Ba 2+ [17][18][19], or Ca 2+ over-buffering [19] enhanced the hypoxia's suppressive effects. Unexpectedly, hypoxia was more effective in suppressing Ca 2+ signaling measured at the RyR2 micro-domains rather than in global cytosolic space, suggesting variable effects of hypoxia on calcium signaling pathway.…”

“…Thus, we conclude that PKA-mediated phosphorylation does not protect the channel against the suppressive effects of hypoxia in hiPSC-CMs. These results are consistent with those reported in adult rat cardiomyocytes [17,18] or in rN-CMs [19] and contrasts sharply with those described for adult guinea pig cardiomyocytes [36].…”

“…transporting calcium channels.-The suppressive effect of acute hypoxia was enhanced from 18% to 35% in adult rat cardiomyocytes when Ba 2+ was charge carrier through the channel [17,18]. Similarly, in rat neonatal cardiomyocytes suppression of CDI by Ba 2+ or by increased intracellular Ca 2+ buffering strongly enhanced the suppressive effects of hypoxia in the rapidly inactivating I Ca cells [19]. Fig.…”

“…Although there are a few reports on the effects of chronic hypoxia in hiPSC-CMs [13][14][15][16], there are no reports on the effects of acute hypoxia and acidosis on calcium signaling of hiPSC-CMs. Since L-type cardiac Ca 2+ channels have been implicated in oxygen-sensing of the rat heart [17] through a mechanism involving the interaction of heme-oxygenase with CaM/CaMKII domain of L-type Ca 2+ channel [18], it was critical to determine whether similar mechanism are also at play in human stem cell-derived cardiomyocytes thus obviating possible subtle species differences in the hypoxic responses and its adrenergic regulation between adult and neonatal rat cardiomyocytes [19] and human heart.…”

Role of mitochondrial Ca2+ homeostasis in cardiac muscles

“…Indeed, using genetically engineered mitochondria-targeted Ca 2+ biosensors, several groups clearly showed that spontaneous beating promotes beat-tobeat mitochondrial Ca 2+ uptake in neonatal cardiomyocytes [14,28]. Moreover, Morad's group also showed that mitochondrial Ca 2+ buffering influences the activity of voltage-gated L-type Ca 2+ channel at the plasma membrane in neonatal cardiomyocytes [127]. Quantitative and simultaneous measurements of cytosolic Ca 2+ and mitochondrial Ca 2+ kinetics combined with appropriate genetic modification of MCU complex activity will help elucidate the contribution of mitochondrial Ca 2+ handing to the formation of Ca 2+ transient in each type of cardiomyocytes.…”