Transient anoxia and oxyradicals induce a region-specific activation of MAPKs in the embryonic heart

Abstract

We have previously reported in the early septating embryonic heart that electromechanical disturbances induced by anoxia-reoxygenation are distinct in atria, ventricle, and outflow tract, and are attenuated in ventricle by opening of mitochondrial K(ATP) (mitoK(ATP)) channels. Here, we assessed the regional activation of mitogen-activated protein kinases (MAPKs) ERK, p38, and JNK in response to anoxia-reoxygenation and H(2)O(2). Hearts isolated from 4-day-old chick embryos were subjected to 30-min anoxia and 60-min reoxygenation or exposed to H(2)O(2) (50 microM-1 mM). The temporal pattern of activation of ERK, p38, and JNK in atria, ventricle, and outflow tract was determined using immunoblotting and/or kinase assay. The effect of the mitoK(ATP) channel opener diazoxide (50 microM) on JNK phosphorylation was also analyzed. Under basal conditions, total ERK and JNK were homogeneously distributed within the heart, whereas total p38 was the lowest in outflow tract. The phosphorylated/total form ratio of each MAPK was similar in all regions. Phosphorylation of ERK increased in atria and ventricle at the end of reoxygenation without change in outflow tract. Phosphorylation of p38 was augmented by anoxia in the three regions, and returned to basal level at the end of reoxygenation except in the outflow tract. JNK activity was not altered by anoxia-reoxygenation in atria and outflow tract. In ventricle, however, the diazoxide-inhibitable peak of JNK activity known to occur during reoxygenation was not accompanied by a change in phosphorylation level. H(2)O(2) over 500 microM impaired cardiac function, phosphorylated ERK in all the regions and p38 in atria and outflow tract, but did not affect JNK phosphorylation. At a critical stage of early cardiogenesis, anoxia, reoxygenation, exogenous H(2)O(2) and opening of mitoK(ATP) channels can subtly modulate ERK, p38, and JNK pathways in a region-specific manner.

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

“…The protein content in the A, V, and OT did not change after 6 h hypoxia relative to normoxia showing that the growth rate was not affected. Our data also show that on the basis of caspase-3 activation, the programmed cell death required for normal cardiac morphogenesis was not increased by 6 h hypoxia in neither A and V nor in OT, which displays the highest apoptotic activity (2,11). Thus, like the embryonic mouse heart (ED9.5) (57), the 4-day-old embryonic chick heart appears to be quite resistant to hypoxia-induced apoptosis.…”

Effect of Remote Ischemic Preconditioning on Phosphorylated Protein Signaling in Children Undergoing Tetralogy of Fallot Repair: A Randomized Controlled Trial

“…The lack of difference in the abundance of phosphorylated signaling proteins between the RIPC and control groups may relate to existing adaptations to chronic hypoxia. Recent data from fetal chick studies indicate that hypoxia and associated ROS directly increase the myocardial activity of MAPK and related signaling proteins, especially in ventricular outflow tract tissues . A qualitative study of right atrial tissue from cyanotic and acyanotic children undergoing surgery for cardiac congenital disorders reported detection of phosphorylated forms of p38MAPK, HSP27, JUN kinase, and protein kinase Cε only in chronically hypoxic patients .…”

“…Recent data from fetal chick studies indicate that hypoxia and associated ROS directly increase the myocardial activity of MAPK and related signaling proteins, especially in ventricular outflow tract tissues. 29 A qualitative study of right atrial tissue from cyanotic and acyanotic children undergoing surgery for cardiac congenital disorders reported detection of phosphorylated forms of p38MAPK, HSP27, JUN kinase, and protein kinase Ce only in chronically hypoxic patients. 30 Thus, any additional benefit of RIPC in ToF may have been abrogated due to preceding adaptive increases in phosphorylated signaling proteins induced by chronic hypoxia.…”

Arrhythmias in the developing heart

“…Under normoxia, H 2 O 2 differentially modulates ERK, p38 and JNK pathways in atria, ventricle and outflow tract (Gardier et al . ). Only exposure to a rather high concentration of H 2 O 2 (>500 μ m ) leads to cardioplegia and markedly increased phosphorylation of ERK2 and p38 specifically in atria and outflow tract, without modifying the level of JNK phosphorylation.…”