title: Tat-biliverdin reductase A protects INS-1 cells from human islet amyloid polypeptide-induced cytotoxicity by alleviating oxidative stress and ER stress.
abstract: Human islet amyloid polypeptide (hIAPP), a major constituent of islet amyloid deposits, induces pancreatic β-cell apoptosis and eventually contributes to β-cell deficit in patients with type 2 diabetes mellitus (T2DM). In this study, Tat-mediated transduction of biliverdin reductase A (BLVRA) was investigated in INS-1 cells to examine whether exogenous supplementation of BLVRA prevented hIAPP-induced apoptosis and dysfunction in insulin secretion in β-cells. Tat-BLVRA fusion protein was efficiently delivered into INS-1 cells in a time- and dose-dependent manner. Exposure of cells to hIAPP induced apoptotic cell death, which was dose-dependently inhibited by pre-treatment with Tat-BLVRA for 1 h. Transduced Tat-BLVRA reduced hIAPP-evoked generation of reactive oxygen species, a crucial mediator of β-cell destruction. Immunoblot analysis showed that Tat-BLVRA suppressed hIAPP-induced increase in the levels of proteins involved in endoplasmic reticulum (ER) stress and apoptosis signaling. Transduced Tat-BLVRA also recovered hIAPP-induced dysfunction in basal and glucose-stimulated insulin secretions. These results suggested that transduced Tat-BLVRA enhanced the tolerance of β-cells against IAPP-induced cytotoxicity by alleviating oxidative stress and ER stress. Therefore, Tat-mediated transduction of BLVRA may provide a potential tool to ameliorate β-cell deficit in pancreas with T2DM.
authors.affiliation: Department of Physiology, College of Medicine, Hallym University, Chuncheon , 24252, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Medicine, Hallym University, Chuncheon , 24252, Republic of Korea.
authors.forename: Hyung Kyung
authors.initials: HK
authors.lastname: Kang
authors.affiliation: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, Republic of Korea.
authors.forename: Won Sik
authors.initials: WS
authors.lastname: Eum
authors.affiliation: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, Republic of Korea.
authors.forename: Jinseu
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Physiology, College of Medicine, Hallym University, Chuncheon , 24252, Republic of Korea.
authors.forename: Hyeok Yil
authors.initials: HY
authors.lastname: Kwon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015696:Gene Products, tat / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D058228:Islet Amyloid Polypeptide / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D014161:Transduction, Genetic
chemical_list: D015696:Gene Products, tat; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D020011:Protective Agents; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
keywords: INS-1 cells; biliverdin reductase A; islet amyloid polypeptide; protein transduction; β-cell apoptosis