Regulation of mitochondrial oxidative stress by β-arrestins in cultured human cardiac fibroblasts

被引:40
作者
Philip, Jennifer L. [1 ]
Razzaque, Md Abdur [1 ]
Han, Mei [1 ]
Li, Jinju [2 ]
Theccanat, Tiju [2 ]
Xu, Xianyao [1 ]
Akhter, Shahab A. [1 ]
机构
[1] Univ Wisconsin, Dept Surg, Div Cardiothorac Surg, Sch Med & Publ Hlth, 600 Highland Ave, Madison, WI 53792 USA
[2] Univ Chicago, Med Ctr, Sect Cardiac & Thorac Surg, Chicago, IL 60637 USA
基金
美国国家卫生研究院;
关键词
beta-arrestin; Oxidative stress; NADPH oxidase; Heart failure; Cardiac fibroblast; Collagen; Myocardial fibrosis; NADPH OXIDASE 4; FIBROTIC RESPONSE; SMAD PATHWAYS; HEART-FAILURE; FAILING HEART; ROLES; DISEASE; DIFFERENTIATION; MYOFIBROBLASTS; HYPERTROPHY;
D O I
10.1242/dmm.019968
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Oxidative stress in cardiac fibroblasts (CFs) promotes transformation to myofibroblasts and collagen synthesis leading to myocardial fibrosis, a precursor to heart failure (HF). NADPH oxidase 4 (Nox4) is a major source of cardiac reactive oxygen species (ROS); however, mechanisms of Nox4 regulation are unclear. beta-arrestins are scaffold proteins that signal in G-protein-dependent and -independent pathways; for example, in ERK activation. We hypothesize that beta-arrestins regulate oxidative stress in a Nox4-dependent manner and increase fibrosis in HF. CFs were isolated from normal and failing adult human left ventricles. Mitochondrial ROS/superoxide production was quantitated using MitoSox. beta-arrestin and Nox4 expressions were manipulated using adenoviral overexpression or short interfering RNA (siRNA)-mediated knockdown. Mitochondrial oxidative stress and Nox4 expression in CFs were significantly increased in HF. Nox4 knockdown resulted in inhibition of mitochondrial superoxide production and decreased basal and TGF-beta-stimulated collagen and alpha-SMA expression. CF beta-arrestin expression was upregulated fourfold in HF. beta-arrestin knockdown in failing CFs decreased ROS and Nox4 expression by 50%. beta-arrestin overexpression in normal CFs increased mitochondrial superoxide production twofold. These effects were prevented by inhibition of either Nox or ERK. Upregulation of Nox4 seemed to be a primary mechanism for increased ROS production in failing CFs, which stimulates collagen deposition. beta-arrestin expression was upregulated in HF and plays an important and newly identified role in regulating mitochondrial superoxide production via Nox4. The mechanism for this effect seems to be ERK-mediated. Targeted inhibition of beta-arrestins in CFs might decrease oxidative stress as well as pathological cardiac fibrosis.
引用
收藏
页码:1579 / 1589
页数:11
相关论文
共 27 条
  • [1] Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes
    Ago, Tetsuro
    Kuroda, Junya
    Pain, Jayashree
    Fu, Cexiong
    Li, Hong
    Sadoshima, Junichi
    [J]. CIRCULATION RESEARCH, 2010, 106 (07) : 1253 - U183
  • [2] Oxidases and peroxidases in cardiovascular and lung disease: New concepts in reactive oxygen species signaling
    Al Ghouleh, Imad
    Khoo, Nicholas K. H.
    Knaus, Ulla G.
    Griendling, Kathy K.
    Touyz, Rhian M.
    Thannickal, Victor J.
    Barchowsky, Aaron
    Nauseef, William M.
    Kelley, Eric E.
    Bauer, Phillip M.
    Darley-Usmar, Victor
    Shiva, Sruti
    Cifuentes-Pagano, Eugenia
    Freeman, Bruce A.
    Gladwin, Mark T.
    Pagano, Patrick J.
    [J]. FREE RADICAL BIOLOGY AND MEDICINE, 2011, 51 (07) : 1271 - 1288
  • [3] Cardiac fibroblasts: friend or foe?
    Baudino, Troy A.
    Carver, Wayne
    Giles, Wayne
    Borg, Thomas K.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2006, 291 (03): : H1015 - H1026
  • [4] Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor β1-induced furin gene transactivation
    Blanchette, F
    Rivard, N
    Rudd, P
    Grondin, F
    Attisano, L
    Dubois, CM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (36) : 33986 - 33994
  • [5] DECREASED CATECHOLAMINE SENSITIVITY AND BETA-ADRENERGIC-RECEPTOR DENSITY IN FAILING HUMAN HEARTS
    BRISTOW, MR
    GINSBURG, R
    MINOBE, W
    CUBICCIOTTI, RS
    SAGEMAN, WS
    LURIE, K
    BILLINGHAM, ME
    HARRISON, DC
    STINSON, EB
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1982, 307 (04) : 205 - 211
  • [6] The cardiac fibroblast: Therapeutic target in myocardial remodeling and failure
    Brown, RD
    Ambler, SK
    Mitchell, MD
    Long, CS
    [J]. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2005, 45 : 657 - 687
  • [7] Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II - Induced cardiac hypertrophy
    Byrne, JA
    Grieve, DJ
    Bendall, JK
    Li, JM
    Gove, C
    Lambeth, JD
    Cave, AC
    Shah, AM
    [J]. CIRCULATION RESEARCH, 2003, 93 (09) : 802 - 804
  • [8] NAD(P)H oxidase 4 mediates transforming growth factor-β1-induced differentiation of cardiac fibroblasts into myofibroblasts
    Cucoranu, I
    Clempus, R
    Dikalova, A
    Phelan, PJ
    Ariyan, S
    Dikalov, S
    Sorescu, D
    [J]. CIRCULATION RESEARCH, 2005, 97 (09) : 900 - 907
  • [9] RETRACTED: G Protein-coupled Receptor Kinase-2 Is a Novel Regulator of Collagen Synthesis in Adult Human Cardiac Fibroblasts (Retracted Article)
    D'Souza, Karen M.
    Malhotra, Ricky
    Philip, Jennifer L.
    Staron, Michelle L.
    Theccanat, Tiju
    Jeevanandam, Valluvan
    Akhter, Shahab A.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (17) : 15507 - 15516
  • [10] GRK mythology: G-protein receptor kinases in cardiovascular disease
    Dorn, Gerald W., II
    [J]. JOURNAL OF MOLECULAR MEDICINE-JMM, 2009, 87 (05): : 455 - 463