Figure 2.

Dual role of p38 activation during preconditioning and ischemia–reperfusion injury. Activation of p38β during preconditioning triggers pro-survival signaling pathways, whereas decreased p38α activation during the ischemic episode leads to cardioprotection. On the other hand, ROS-induced p38α activation during the ischemic insult triggers HIF1-α stabilization; increases (↑) fibrosis, arrhythmias, and inflammation; and disrupts mitochondrial homeostasis. SB203580 administration during preconditioning increases myocardial injury, whereas administration during ischemia–reperfusion improves cardiac outcome. Indirect p38 downregulators, such as gamboge, statins, and antioxidants, seem to have beneficial effects when administered during or after the ischemia. Further research is needed to determine the precise reciprocity of ROS–p38 regulation. ↑ increase.