Regulation of Ca(2+) signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells.

AIMS: The effects of acute (100 s) hypoxia and/or acidosis on Ca(2+) signaling parameters of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are explored here for the first time. METHODS AND RESULTS: 1) hiPSC-CMs express two cell populations: rapidly-inactivating I(Ca) myocytes (τ(i)<40 ms, in 4-5 day cultures) and slowly-inactivating I(Ca) (τ(i)  ≥ 40 ms, in 6-8 day cultures). 2) Hypoxia suppressed I(Ca) by 10-20% in rapidly- and 40-55% in slowly-inactivating I(Ca) cells. 3) Isoproterenol enhanced I(Ca) in hiPSC-CMs, but either enhanced or did not alter the hypoxic suppression. 4) Hypoxia had no differential suppressive effects in the two cell-types when Ba(2+) was the charge carrier through the calcium channels, implicating Ca(2+)-dependent inactivation in O(2) sensing. 5) Acidosis suppressed I(Ca) by ∼35% and ∼25% in rapidly and slowly inactivating I(Ca) cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was ∼25% in global and ∼37% in RyR2 Ca(2+)-microdomains in either cell type, whereas with hypoxia suppression was ∼20% and ∼25% respectively in global and RyR2-microdomaine in rapidly and ∼35% and ∼45% respectively in global and RyR2-microdomaine in slowly-inactivating cells. CONCLUSIONS: Variability in I(Ca) inactivation kinetics rather than cellular ancestry seems to underlie the action potential morphology differences generally attributed to mixed atrial and ventricular cell populations in hiPSC-CMs cultures. The differential hypoxic regulation of Ca(2+)-signaling in the two-cell types arises from differential Ca(2+)-dependent inactivation of the Ca(2+)-channel caused by proximity of Ca(2+)-release stores to the Ca(2+) channels.