Bin Wei1, Fenghe Li2. 1. Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China. 2. Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Abstract
OBJECTIVE: Apoptotic events mediated by mitochondrial injury play an important role on the onset of Pemphigus vulgaris (PV). The thioredoxin-2 (Trx2)/apoptosis signal-regulating kinase 1 (ASK1) signaling pathway is considered a key cascade involved on the regulation of mitochondrial injury. Hence, we have investigated the regulatory mechanism of the Trx2/ASK1 signaling in PV-induced mitochondrial injury. METHODS: Serum and tissue samples were collected from clinical PV patients to detect the oxidative stress factors, cell apoptosis, and expression of members from Trx2/ASK1 signaling. HaCaT cells were cultured with the serum of PV patients and transfected with Trx2 overexpression or silencing vector. Changes in the levels of reactive oxygen species (ROS), mitochondrial membrane potential (△ψm), and apoptosis were further evaluated. A PV mouse model was established and administered with Trx2-overexpressing plasmid. The effect of ectopic Trx2 expression towards acantholysis in PV mice was observed. RESULTS: A series of cellular and molecular effects, including (i) increased levels of oxidative stress products, (ii) destruction of epithelial cells in the skin tissues, (iii) induction of apoptosis in keratinocytes, (iv) reduction of Trx2 protein levels, and (v) enhanced phosphorylation of ASK1, were detected in PV patients. In vitro experiments confirmed that Trx2 can inhibit ASK1 phosphorylation, alleviate ROS release, decrease △ψm, and lower the apoptotic rate. Injection of Trx2-overexpressing vectors in vivo could also relieve acantholysis and blister formation in PV mice. CONCLUSION: The Trx2/ASK1 signaling pathway regulates the incidence of PV mediated by mitochondrial injury.
OBJECTIVE: Apoptotic events mediated by mitochondrial injury play an important role on the onset of Pemphigus vulgaris (PV). The thioredoxin-2 (Trx2)/apoptosis signal-regulating kinase 1 (ASK1) signaling pathway is considered a key cascade involved on the regulation of mitochondrial injury. Hence, we have investigated the regulatory mechanism of the Trx2/ASK1 signaling in PV-induced mitochondrial injury. METHODS: Serum and tissue samples were collected from clinical PV patients to detect the oxidative stress factors, cell apoptosis, and expression of members from Trx2/ASK1 signaling. HaCaT cells were cultured with the serum of PV patients and transfected with Trx2 overexpression or silencing vector. Changes in the levels of reactive oxygen species (ROS), mitochondrial membrane potential (△ψm), and apoptosis were further evaluated. A PV mouse model was established and administered with Trx2-overexpressing plasmid. The effect of ectopic Trx2 expression towards acantholysis in PV mice was observed. RESULTS: A series of cellular and molecular effects, including (i) increased levels of oxidative stress products, (ii) destruction of epithelial cells in the skin tissues, (iii) induction of apoptosis in keratinocytes, (iv) reduction of Trx2 protein levels, and (v) enhanced phosphorylation of ASK1, were detected in PV patients. In vitro experiments confirmed that Trx2 can inhibit ASK1 phosphorylation, alleviate ROS release, decrease △ψm, and lower the apoptotic rate. Injection of Trx2-overexpressing vectors in vivo could also relieve acantholysis and blister formation in PV mice. CONCLUSION: The Trx2/ASK1 signaling pathway regulates the incidence of PV mediated by mitochondrial injury.
Authors: John T Liles; Britton K Corkey; Gregory T Notte; Grant R Budas; Eric B Lansdon; Ford Hinojosa-Kirschenbaum; Shawn S Badal; Michael Lee; Brian E Schultz; Sarah Wise; Swetha Pendem; Michael Graupe; Laurie Castonguay; Keith A Koch; Melanie H Wong; Giuseppe A Papalia; Dorothy M French; Theodore Sullivan; Erik G Huntzicker; Frank Y Ma; David J Nikolic-Paterson; Tareq Altuhaifi; Haichun Yang; Agnes B Fogo; David G Breckenridge Journal: J Clin Invest Date: 2018-07-19 Impact factor: 14.808
Authors: Mina Kalantari-Dehaghi; Grant J Anhalt; Michael J Camilleri; Alex I Chernyavsky; Sookhee Chun; Philip L Felgner; Algis Jasinskas; Kristin M Leiferman; Li Liang; Steve Marchenko; Rie Nakajima-Sasaki; Mark R Pittelkow; John J Zone; Sergei A Grando Journal: PLoS One Date: 2013-03-07 Impact factor: 3.240