title: Angiotensin II type I receptor agonistic autoantibody-induced apoptosis in neonatal rat cardiomyocytes is dependent on the generation of tumor necrosis factor-α.
abstract: Angiotensin II type I receptor agonistic autoantibodies (AT1-AA) are related to pre-eclampsia and hypertension and have a direct effect of stimulating the production of tumor necrosis factor-alpha (TNF-α) in the placenta. TNF-α is a known mediator of apoptosis. However, few studies have reported the role of TNF-α and its relationship within AT1-AA-induced apoptosis of cardiomyocytes. In this study, neonatal rat cardiomyocytes were treated with various concentrations of AT1-AA. The apoptosis of neonatal rat cardiomyocytes was determined using TUNEL assay and flow cytometry. The level of secreted TNF-α was measured by enzyme-linked immunosorbent assay, and caspase-3 activity was measured by a fluorogenic protease assay kit. AT1 receptor blockade and TNF inhibitor were added to determine whether they could inhibit the apoptotic effect of AT1-AA. Results showed that AT1-AA induced the apoptosis of neonatal rat cardiomyocytes in a dose-dependent and time-dependent manner. AT1-AA increased TNF secretion and caspase-3 activities. AT1 receptor blockade completely abrogated AT1-AA-induced TNF-α secretion, caspase-3 activation, and cardiomyocyte apoptosis. TNF-α receptor inhibitor significantly attenuated AT1-AA-induced neonatal rat cardiomyocyte apoptosis. AT1-AA in the plasma of pre-eclamptic patients promoted neonatal rat cardiomyocyte apoptosis through a TNF-caspase signaling pathway.
authors.affiliation: Department of Assisted Reproductive Technology,  Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011,  China.
authors.forename: Weiran
authors.initials: W
authors.lastname: Chai
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhu
authors.initials: Z
authors.lastname: Jin
authors.forename: Yiping
authors.initials: Y
authors.lastname: Feng
authors.forename: Yanping
authors.initials: Y
authors.lastname: Kuang
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011225:Pre-Eclampsia / Q000097:blood / Q000276:immunology; D011247:Pregnancy; D051381:Rats; D011945:Receptors, Angiotensin / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3