title: Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols.
abstract: Oxysterols, oxygenated derivatives of cholesterol, are found abundantly in the plasma and atherosclerotic plaques, a common risk factor for thoracic aortic aneurysms (TAAs). Among the oxysterols, namely 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC), lead both to induction of reactive oxygen species (ROS) in cells and to apoptosis in smooth muscle cells (SMCs) probably due to increased oxidative stress. Since loss of SMCs through apoptosis is a major event in TAA formation, it is important to understand the molecular pathways of apoptosis in response to ROS in TAAs. Very little is known about the effect of oxysterols on TAA SMCs. Therefore, we investigated molecular pathways participating in the oxysterol induced cell death of TAAs. Our results showed that TAA SMCs died mainly as a result of apoptosis as suggested by cellular shrinkage, blebbing, DNA condensation/fragmentation in response to oxysterol treatment. There was no significant difference in oxysterol induced cell death between TAA and control SMCs. Addition of antioxidant molecules prevented cell death, hence ROS appears to be involved in the apoptosis of these cells. While oxysterol treatment increased caspase 3 activity, cell death was not rescued in its absence. Efficient silencing of other targets including apoptotic proteins (p53, Bax), and survival proteins (Akt1, Akt2) showed that apoptosis can occur through p53, and Bax independent pathways. Silencing Akt1 or Akt2 did not lead to further cell death. These results indicate that oxysterols can induce several cell death pathways in TAA SMCs.
authors.affiliation: TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, 41470, Gebze, Kocaeli, Turkey.
authors.forename: Zelal
authors.initials: Z
authors.lastname: Adiguzel
authors.forename: Nazli
authors.initials: N
authors.lastname: Arda
authors.forename: Omer
authors.initials: O
authors.lastname: Kacar
authors.forename: Muge
authors.initials: M
authors.lastname: Serhatli
authors.forename: Serpil
authors.initials: S
authors.lastname: Gezer Tas
authors.forename: Ahmet Tarik
authors.initials: AT
authors.lastname: Baykal
authors.forename: Kemal
authors.initials: K
authors.lastname: Baysal
authors.forename: Ceyda
authors.initials: C
authors.lastname: Acilan
mesh_terms: D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007653:Ketocholesterols / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006888:Hydroxycholesterols; D007653:Ketocholesterols; D017382:Reactive Oxygen Species; C007997:25-hydroxycholesterol; D002784:Cholesterol; C505407:CASP3 protein, human; D053148:Caspase 3; C003001:7-ketocholesterol