Survival signals induced by cholesterol oxidation by-products in atherosclerosis

Official URL: http://risc01.sabanciuniv.edu/record=b1620375 (Table of Contents)

Atherosclerosis is the most prevalent cause of morbidity and mortality developed countries. Oxysterols are a family of 27-carbon molecules originated from cholesterol oxidation and the atherogenic potential of oxysterols is linked to their ability to induce apoptosis, vascular smooth muscle cell proliferation and monocyte migration. Apparently, these compounds are able to modulate not only pro-apoptotic but also antiapoptotic signals in targeted cells; however, their anti-apoptotic effect has not been investigated in depth. Hence, we aimed to elucidate the molecular mechanisms underlying the survival signaling elicited by 27-hydroxycholesterol (27-OH) which is the most represented oxysterol in human blood. Using human promonocytic cells (U937) challenged with a relatively low (10 uM) concentration of 27-OH, a marked while transient increase of intracellular ROS level that enhanced both MEK-ERK and PI3K-Akt phosphorylation was observed between 6 and 24 hours, paralleled by Bad phosphorylation, resulting to be a crucial event in delaying apoptotic death. In turn, the knock down of ERK and Akt by means of selective inhibitors, increased ROS production at 12 h showing that ERK/Akt axis was responsible of a sustained quenching of ROS production. Involvement of antioxidant Nrf2 and its target genes, HO-1 and NQO-1 in this early survival response were shown. It thus appears that Nrf2 is responsible for the quenching of the oxidative imbalance exerted in 27-OH challenged cells that analyzed by confocal microscopy. The data obtained highlight oxysterols' ability to promote cell survival that might contribute to the pathogenesis of inflammation-driven chronic diseases such as atherosclerosis.