title: NADPH oxidases mediate a cellular "memory" of angiotensin II stress in hypertensive cardiac hypertrophy.
abstract: A long-term "memory" of hyperglycemic stress, even when glycemia is normalized, has been previously reported in diabetes. In this report we propose a similar hypothesis that exposure to continuous high angiotensin II (Ang II) results in a cellular "memory" in isolated cardiomyocytes and in the heart tissues, and we investigate the role of NADPH oxidases in this phenomenon. Continuous high Ang II for 3 days markedly increased cardiomyocyte size, TUNEL-positive apoptotic cardiomyocytes, expression of inflammatory cytokines, and oxidative stress. These deleterious effects were also observed in the memory condition (high Ang II for 2 days followed by normal medium for 1 day). Furthermore, in a mouse model, Ang II infusion for 3 weeks significantly increased cardiac hypertrophy, apoptosis, inflammation, and ROS generation but decreased cardiac function compared with control mice, and similar effects were also observed in mice in the memory condition. Importantly, blockade of NADPH oxidase using apocynin diminished the induction of high Ang II stress markers in isolated cardiomyocytes and in the mouse heart. These effects were associated with inhibition of NADPH oxidase-mediated AKT/mTOR/S6K and ERK signaling pathways. The present results demonstrate the hypothesis that exposure to continuous high Ang II results in a hypertensive cellular memory that remains, even when cells or mice are switched back to normal Ang II. This phenomenon was associated with NADPH oxidase-mediated oxidative stress.
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Qiu-Yue
authors.initials: QY
authors.lastname: Han
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Tian
authors.affiliation: Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Physiology and Pathophysiology, Beijing AnZhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing 100069, China. Electronic address: hhli1995@yahoo.com.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D006973:Hypertension / Q000150:complications / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases
keywords: Angiotensin II; Cardiac hypertrophy; Free radicals; NADPH oxidases