Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

Figure 3

Simplified scheme of the EP4 signaling in PGE₂-mediated hypertrophic actions. In response to PGE₂, activation of EP4 transactivates epidermal growth factor receptors (EGFR), which can result in the activation of extracellular signal-regulated kinases (ERK1/2). ERK1/2 in turn activated signal transducer and activator of transcription 3 (Stat3) pathway. Once Stat3 signaling is activated in the nucleus, the hypertrophic genes will be expressed to mediate the protein synthesis. In addition, cyclooxygenase-2 (COX-2) expression is also stimulated by Stat3 signaling, which will further metabolize the formation of PGE₂ from arachidonic acid (AA) and trigger the greater activation of Stat3 signaling in a positive feedback loop. Cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) or cAMP/exchange protein directly activated by cAMP (Epac) pathways are not involved in the PGE₂-EP4-mediated hypertrophic actions in ventricular myocytes.