Apoptosis is now known to be an important regulator of maintaining normal organ homeostasis. However, in recent years experimental studies support the concept that excessive alveolar epithelial cell (AEC) apoptosis contributes to pathogenic conditions in lung. Studies show that local activation of angiotensin system (ANG) in the lung plays a major role in AEC apoptosis. Autocrine generation of angiotensin II (ANGII) an effector peptide, initiates AEC apoptosis through AT1 receptor, phosphorylating c-Jun-N-terminal kinase (pJNK), both of which are required events in AEC apoptosis. Angiotensin converting enzyme-2 (ACE-2) is a vital enzyme that converts ANGII to angiotensin 1-7 (ANG1-7), promoting cell survival by limiting the accumulation of ANGII. Although the downstream signaling mechanisms of ANG1-7/Mas are unclear, experimental studies have shown anti-apoptotic effects of ANG1-7 in AECs.In this study, the molecular mechanisms by which ANG1-7 and its receptor Mas promote AEC survival are investigated. Previous studies from the Uhal laboratory indicated that under normal conditions ANG1-7 levels are higher than ANGII levels in the AEC culture. Hence, it was theorized that ANG1-7 activates a map kinase phosphatase-2 (MKP-2) and maintains low pJNK levels, as a cell survival mechanism in AECs.The data show blockade of the Mas receptor diminished the induction of MKP-2 by ANG1-7 which confirmed that Mas acts through MKP-2. Further, silencing MKP-2 abolished the ability of ANG1-7 to block ANGII-induced phospho-JNK and apoptosis. Silencing of MKP-2 significantly prevented the blockade of all apoptotic markers such as caspase-9, loss of mitochondrial membrane potential (MMP) and DNA fragmentation by ANG1-7. These data support the theory that ANG1-7 upregulates the phosphatase MKP-2 through Mas and thereby maintains low phospho-JNK levels to promote AEC survival.In conclusion, this study implies that ANG1-7/Mas activation inhibits JNK phosphorylation and apoptosis by constitutively activating MKP-2, and further demonstrates the critical role of the ANG1-7 receptor Mas in AEC survival.
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