Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation

Prostaglandin E(2) (PGE(2)) synthesis modulates the response to radiation injury in the mouse intestinal epithelium through effects on crypt survival and apoptosis; however, the downstream signaling events have not been elucidated. WT mice receiving 16,16-dimethyl PGE(2) (dmPGE(2)) had fewer apoptotic cells per crypt than untreated mice. Apoptosis in Bax(–/–) mice receiving 12 Gy was approximately 50% less than in WT mice, and the ability of dmPGE(2) to attenuate apoptosis was lost in Bax(–/–) mice. Positional analysis revealed that apoptosis in the Bax(–/–) mice was diminished only in the bax-expressing cells of the lower crypts and that in WT mice, dmPGE(2) decreased apoptosis only in the bax-expressing cells. The HCT-116 intestinal cell line and Bax(–/–) HCT-116 recapitulated the apoptotic response of the mouse small intestine with regard to irradiation and dmPGE(2). Irradiation of HCT-116 cells resulted in phosphorylation of AKT that was enhanced by dmPGE(2) through transactivation of the EGFR. Inhibition of AKT phosphorylation prevented the reduction of apoptosis by dmPGE(2) following radiation. Transfection of HCT-116 cells with a constitutively active AKT reduced apoptosis in irradiated cells to the same extent as in nontransfected cells treated with dmPGE(2). Treatment with dmPGE(2) did not alter bax or bcl-x expression but suppressed bax translocation to the mitochondrial membrane. Our in vivo studies indicate that there are bax-dependent and bax-independent radiation-induced apoptosis in the intestine but that only the bax-dependent apoptosis is reduced by dmPGE(2). The in vitro studies indicate that dmPGE(2), most likely by signaling through the E prostaglandin receptor EP(2), reduces radiation-induced apoptosis through transactivation of the EGFR and enhanced activation of AKT and that this results in reduced bax translocation to the mitochondria

Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury