title: HIV Tat protein inhibits hERG K+ channels: a potential mechanism of HIV infection induced LQTs.
abstract: HIV-infected patients have a high prevalence of long QT syndrome (LQTs). hERG K(+) channel encoded by human ether-a-go-go related gene contributes to IKr K(+) currents responsible for the repolarization of cardiomyocytes. Inhibition of hERG K(+) channels leads to LQTs. HIV Tat protein, the virus transactivator protein, plays a pivotal role in AIDS. The aim of the present study is to examine the effects of HIV Tat protein on hERG K(+) channels stably expressed in HEK293 cells. The hERG K(+) currents were recorded by whole-cell patch-clamp technique and the hERG channel expression was measured by real-time PCR and Western blot techniques. HIV Tat protein at 200 ng/ml concentration showed no acute effect on hERG currents, but HIV Tat protein (200 ng/ml) incubation for 24 h significantly inhibited hERG currents. In HIV Tat incubated cells, the inactivation and the recovery time from inactivation of hERG channels were significantly changed. HIV Tat protein incubation (200 ng/ml) for 24h had no effect on the hERG mRNA expression, but dose-dependently inhibited hERG protein expression. The MTT assay showed that HIV Tat protein at 50 ng/ml and 200 ng/ml had no effect on the cell viability. HIV Tat protein increased reactive oxygen species (ROS) generation and the inhibition of hERG channel protein expression by HIV Tat protein was prevented by antioxidant tempol. HIV Tat protein in vivo treatment reduced IKr currents and prolonged action potential duration of guinea pig cardiomyocytes. We conclude that HIV Tat protein inhibits hERG K(+) currents through the inhibition of hERG protein expression, which might be the potential mechanism of HIV infection induced LQTs.
authors.affiliation: Department of Pharmacology the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin 150086, PR China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Bai
authors.forename: Hui-Bin
authors.initials: HB
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Chao-Wei
authors.initials: CW
authors.lastname: Hu
authors.forename: Jiu-Xin
authors.initials: JX
authors.lastname: Zhu
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Gong
authors.forename: Xue
authors.initials: X
authors.lastname: Teng
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006678:HIV / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000821:virology; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013113:Spin Labels; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000009:adverse effects*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013113:Spin Labels; D054322:tat Gene Products, Human Immunodeficiency Virus; C001803:tempol