Reactive astrogliosis is a hallmark of many neurological disorders, yet its functions and molecular mechanisms remain elusive. Particularly, the upstream signaling that regulates pathological responses of astrocytes is largely undetermined. We used a mouse traumatic brain injury model to induce astrogliosis and revealed activation of ErbB receptors in reactive astrocytes. Moreover, cell-autonomous inhibition of ErbB receptor activity in reactive astrocytes by a genetic approach suppressed hypertrophic remodeling possibly through the regulation of actin dynamics. However, inhibiting ErbB signaling in reactive astrocytes did not affect astrocyte proliferation after brain injury, although it aggravated local inflammation. In contrast, active ErbB signaling in mature astrocytes of various brain regions in mice was sufficient to initiate reactive responses, reproducing characterized molecular and cellular features of astrogliosis observed in injured or diseased brains. Further, prevalent astrogliosis in the brain induced by astrocytic ErbB activation caused anorexia in animals. Therefore, our findings defined an unrecognized role of ErbB signaling in inducing reactive astrogliosis. Mechanistically, inhibiting ErbB signaling in reactive astrocytes prominently reduced Src and focal adhesion kinase (FAK) activity that is important for actin remodeling, although ErbB signaling activated multiple downstream signaling proteins. The discrepancies between the results from loss- and gain-of-function studies indicated that ErbB signaling regulated hypertrophy and proliferation of reactive astrocytes by different downstream signaling pathways. Our work demonstrated an essential mechanism in the pathological regulation of astrocytes and provided novel insights into potential therapeutic targets for astrogliosis-implicated diseases.

To date, hypoxia-inducible factor 1a (HIF-1a) and astrocyte elevated gene-1 (AEG-1) have been involved in the proliferation, migration and morphological changes of vascular smooth muscle cells. However, the potential relationship of HIF-1a-AEG-1 pathway in human aortic smooth muscle cell (HASMC) has not been reported. In the present study, in-vitro assays were utilized to explore the potential impact of HIF-1a-AEG-1 signaling on HASMC phenotype. Here, we found that HIF-1a expression was up-regulated in the media of thoracic aortic dissection tissues as compared with normal aortic tissues, and was associated with increased apoptotic SMCs and decreased AEG-1 expression. Mechanically, hypoxia promoted the expression of HIF-1a by PI3K-AKT pathway in HASMCs; HIF-1a further suppressed the expressions of AEG-1, a-SMA and SM22a, and promoted osteopontin (OPN) expression. Functionally, HIF-1a inhibited the proliferation and migration of HASMCs. However, si-HIF-1a or Akt inhibitor abrogated HIF-1a-mediated related expressions and biological effects above. In conclusion, HIF-1a induces HASMC phenotype switch, and closely related to PI3K/AKT and AEG-1 signaling, which may provide new avenues for the prevention and treatment of aortic dissection diseases.

Postoperative oxygenation impairment is a common complication of surgery for type-A acute aortic dissection. Body mass index, preoperative oxygenation impairment, preoperative homocysteine, circulatory arrest time, and plasma transfusion were independent risk factors for oxygenation impairment after a total arch replacement procedure.

Recently, astrocyte-elevated gene-1 (AEG-1) and insulin-like growth factor 1 (IGF-1) have been involved in the regulation of multiple signaling pathways in tumorigenesis. To date, the detailed mechanisms underlying IGF-1-AEG-1 pathway-induced proliferation and apoptosis in cardiac myxoma (CM) was not reported. In the present study, we used immnohistochemistry, immunoblotting, and qRT-PCR to detect the expression profile of IGF-1 and AEG-1 in 90 CM tissues, and then cultured CM cells were subjected to si-AEG-1, in vitro, and in vivo assays. Our findings showed that IGF-1 and AEG-1 were obviously upregulated in CM tissues and markedly associated with tumor size. When CM cells were treated with si-AEG-1, si-AEG-1 attenuated IGF-1-induced CM cell growth and enhanced cell apoptosis. Mechanically, we validated the expression of AEG-1, p-Erk1/2, and p-Akt increased in CM cells in response to IGF-1 treatment in a time-dependent manner. However, si-AEG-1 affected the expression of these proteins. Functionally, we found the knockdown of AEG-1-inhibited G1/S transition and tumor formation of CM cells. In conclusion, AEG-1 regulates IGF-1-induced proliferation and apoptosis via Erk1/2 and Akt signaling in CM development, which suggests IGF-1-AEG-1 signaling could be recommended to be a useful target to exert anti-tumor effects on CM.