title: Propofol protects against angiotensin II-induced mouse hippocampal HT22 cells apoptosis via inhibition of p66Shc mitochondrial translocation.
abstract: Hippocampal neuronal oxidative stress and apoptosis have been reported to be involved in cognitive impairment, and angiotensin II could induce hippocampal oxidative stress and apoptosis. Propofol is a widely used intravenous anesthetic agent in clinical practice, and it demonstrates significant neuroprotective activities. In this study, we investigated the mechanism how propofol protected mouse hippocampal HT22 cells against angiotensin II-induced oxidative stress and apoptosis. Cell viability was evaluated with CCK8 kit. Protein expressions of active caspase 3, cytochrome c, p66(Shc), p-p66(shc)-Ser(36), protein kinase C βII (PKCβII), Pin-1 and phosphatase A2 (PP2A) were measured by Western blot. Superoxide anion (O2(.-)) accumulation was measured with the reduction of ferricytochrome c. Compared with the control group, angiotensin II up-regulated expression of PKCβII, Pin-1 and PP2A, induced p66(Shc)-Ser(36) phosphorylation, and facilitated p66(Shc) mitochondrial translocation, resulting in O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, and the inhibition of cell viability. Importantly, we found propofol inhibited angiotensin II-induced PKCβII and PP2A expression and improved p66(Shc) mitochondrial translocation, O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, inhibition of cell viability. On the other hand, propofol had no effects on angiotensin II-induced Pin-1 expression and p66(Shc)-Ser(36) phosphorylation. Moreover, the protective effects of propofol on angiotensin II-induced HT22 apoptosis were similar with calyculin A, an inhibitor of PP2A and CGP53353, an inhibitor of PKCβII. However, the protective effect of propofol could be reversed by FTY720, an activator of PP2A, rather than PMA, an activator of PKCβII. Our data indicated that propofol down-regulated PP2A expression, inhibiting dephosphorylation of p66(Shc)-Ser(36) and p66(Shc) mitochondrial translocation, decreasing O2(.-) accumulation, reducing mitochondrial cytochrome c release, inhibiting caspase 3 activation. By these mechanisms, it protects mouse hippocampal HT22 cells against angiotensin II-induced apoptosis.
authors.affiliation: Department of Anesthesiology, Fudan University Shanghai Cancer Center, No 270 DongAn Road, Shanghai, 200032, People's Republic of China, natalie7901@126.com.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhu
authors.forename: Jiawei
authors.initials: J
authors.lastname: Chen
authors.forename: Meilin
authors.initials: M
authors.lastname: Wen
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Sun
authors.forename: Xia
authors.initials: X
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Changhong
authors.initials: C
authors.lastname: Miao
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D019696:Peptidylprolyl Isomerase / Q000096:biosynthesis / Q000235:genetics; D015742:Propofol / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides; D000804:Angiotensin II; D045304:Cytochromes c; D064546:Protein Kinase C beta; D054648:Protein Phosphatase 2; C505409:Casp3 protein, mouse; D053148:Caspase 3; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D015742:Propofol