Cellular Mechanisms of Cardiac Depression and Recovery in Endotoxemic Mice

Abstract

Sepsis and septic shock are associated with a reversible cardiac dysfunction, that complicates management and worsens prognosis. In patients that survive septic shock, cardiac function recovers spontaneously, through mechanisms that are currently unknown. Here we aimed to identify the intracellular calcium (Ca2+) transporters responsible for cardiac recovery after endotoxemic challenge in mice. Male C57Bl6 mice were administered lipopolysaccharide (LPS, 7 μg/g weight, ip). 12h after LPS administration, cardiomyocyte sarcomere shortening (SS) and Ca2+ transients (ΔCai, measured with fura2-AM) were decreased to 53 ± 10% and 78 ± 5% of control, respectively, in association with a decrease in trans-sarcolemmal Ca2+ influx (Cainf) through the L-type Ca2+ channels (LTCC, to 65± 9%) and sarcoplasmic reticulum (SR) Ca2+ pump (SERCA) reuptake (88 ± 5%, n > 19 cells from 3 mice for all). SR Ca2+ load (CaSR, measured with caffeine) was unchanged, while SR fractional release (FR, as αCai/CaSR) was decreased to 84 ± 6% of control (n's as above). 72h after LPS administration, survival was 40%. In cells isolated from surviving mice 72h after LPS, ΔCa, FR and Cainf were fully recovered, while SERCA showed a supranormal function (138 ± 4% of control, n's as above). SS showed a trend towards a partial depression (to 82 ± 7% of control, p = 0.077, n's as above) at 72h, that persisted up to 6 days after LPS administration. In conclusion, the recovery of cardiac Ca2+ handling after LPS challenge is associated with a full recovery of LTCC dysfunction, a supranormal activation of SERCA, despite, possibly, a persistent dysfunction in the contractile mechanisms downstream of the Ca2+ transient.