Figure 7.

Schematic illustration of AMPK and MDM2-modulated the phosphorylation and ubiquitination of ACE2 in PAH. In functional pulmonary endothelial cells or those under metformin therapy, AMPK phosphorylates ACE2 at S680 to increase its stability to maintain the eNOS-derived nitric oxide bioavailability. As an E3 ligase of ACE2, MDM2 ubiquitinates ACE2 at K788, resulting in its degradation under hypoxia, thereby inducing disorder of RAS system and dysfunction of ECs, eventually lead to PAH. Such pathological modulation may be reversed by JNJ-165 therapy, which inhibits the MDM2 E3 function. ACE2 indicates angiotensin-converting enzyme 2; AMPK, AMP-activated protein kinase; Ang, angiotensin; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; MDM2, murine double minute 2; PAH, pulmonary arterial hypertension; RAS, renin-angiotensin system; and Ub, ubiquitin.