Molecular mechanisms in H2O2-induced increase in AT1 receptor gene expression in cardiac fibroblasts: A role for endogenously generated Angiotensin II

被引:15
作者
Anupama, V. [1 ]
George, Mereena [1 ]
Dhanesh, Sivadasan Bindu [2 ]
Chandran, Aneesh [3 ]
James, Jackson [2 ]
Shivakumar, K. [1 ]
机构
[1] Sree Chitra Tirunal Inst Med Sci & Technol, Div Cellular & Mol Cardiol, Trivandrum 695011, Kerala, India
[2] Rajiv Gandhi Ctr Biotechnol, Div Neurobiol, Neuro Stem Cell Biol, Trivandrum 695014, Kerala, India
[3] Rajiv Gandhi Ctr Biotechnol, Bacterial & Parasite Dis Biol, Trop Dis Biol, Trivandrum 695014, Kerala, India
关键词
Cardiac fibroblasts; AT1R; Oxidative stress; Angiotensin II; Collagen; NF-KAPPA-B; SMOOTH-MUSCLE-CELLS; OXIDATIVE STRESS INCREASES; AT(1) RECEPTOR; HEART-FAILURE; UP-REGULATION; DEPENDENT REGULATION; TYPE-1; RECEPTOR; ERK1/2; MAPK; P38;
D O I
10.1016/j.yjmcc.2016.05.010
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The AT1 receptor (AT1R) mediates the manifold actions of angiotensin II in the cardiovascular system. This study probed the molecular mechanisms that link altered redox status to AT1R expression in cardiac fibroblasts. Real-time PCR and western blot analysis showed that H2O2 enhances AT1R mRNA and protein expression via NADPH oxidase-dependent reactive oxygen species induction. Activation of NF-kappa B and AP-1, demonstrated by electrophoretic mobility shift assay, abolition of AT1R expression by their inhibitors, Bay-11-7085 and SR11302, respectively, and luciferase and chromatin immunoprecipitation assays confirmed transcriptional control of AT1R by NF-kappa B and AP-1 in H2O2-treated cells. Further, inhibition of ERK1/2, p38 MAPK and c-Jun N-terminal kinase (JNK) using chemical inhibitors or by RNA interference attenuated AT1R expression. Inhibition of the MAPKs showed that while ERK1/2 and p38 MAPK suffice for NF-kappa B activation, all three kinases are required for AP-1 activation. H2O2 also increased collagen type I mRNA and protein expression. Interestingly, the AT1R antagonist, candesartan, attenuated H2O2-stimulated AT1R and collagen mRNA and protein expression, suggesting that H2O2 up-regulates AT1R and collagen expression via local Angiotensin II generation, which was confirmed by real-time PCR and ELISA. To conclude, oxidative stress enhances AT1R gene expression in cardiac fibroblasts by a complex mechanism involving the redox-sensitive transcription factors NF-kappa B and AP-1 that are activated by the co-ordinated action of ERK1/2, p38 MAPK and JNK. Importantly, by causally linking oxidative stress to Angiotensin II and AT1R up-regulation in cardiac fibroblasts, this study offers a novel perspective on the pathogenesis of cardiovascular diseases associated with oxidative stress. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码:295 / 305
页数:11
相关论文
共 57 条
  • [1] Alderman M.H., 2004, Circulation, V110, pe496
  • [2] Tissue renin-angiotensin systems:: new insights from experimental animal models in hypertension research
    Bader, J
    Peters, J
    Baltatu, O
    Müller, DN
    Luft, FC
    Ganten, D
    [J]. JOURNAL OF MOLECULAR MEDICINE-JMM, 2001, 79 (2-3): : 76 - 102
  • [3] Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension
    Banday, Anees Ahmad
    Lokhandwala, Mustafa F.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2008, 295 (03) : F698 - F706
  • [4] Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy
    Bang, Claudia
    Batkai, Sandor
    Dangwal, Seema
    Gupta, Shashi Kumar
    Foinquinos, Ariana
    Holzmann, Angelika
    Just, Annette
    Remke, Janet
    Zimmer, Karina
    Zeug, Andre
    Ponimaskin, Evgeni
    Schmiedl, Andreas
    Yin, Xiaoke
    Mayr, Manuel
    Halder, Rashi
    Fischer, Andre
    Engelhardt, Stefan
    Wei, Yuanyuan
    Schober, Andreas
    Fiedler, Jan
    Thum, Thomas
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (05) : 2136 - 2146
  • [5] Canine ventricular myocytes possess a renin-angiotensin system that is upregulated with heart failure
    Barlucchi, L
    Leri, A
    Dostal, DE
    Fiordaliso, F
    Tada, H
    Hintze, TH
    Kajstura, J
    Nadal-Ginard, B
    Anversa, P
    [J]. CIRCULATION RESEARCH, 2001, 88 (03) : 298 - 304
  • [6] 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
  • [7] Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B
    Bhatt, Siddhartha R.
    Lokhandwala, Mustafa F.
    Banday, Anees Ahmad
    [J]. CLINICAL AND EXPERIMENTAL HYPERTENSION, 2014, 36 (06) : 367 - 373
  • [8] Renin-angiotensin system mediated mechanisms: cardioreparation and cardioprotection
    Brilla, CG
    [J]. HEART, 2000, 84 : I18 - I19
  • [9] Pathological Ventricular Remodeling: Mechanisms: Part 1 of 2
    Burchfield, Jana S.
    Xie, Min
    Hill, Joseph A.
    [J]. CIRCULATION, 2013, 128 (04) : 388 - 400
  • [10] H2O2 activates Nox4 through PLA2-dependent arachidonic acid production in adult cardiac fibroblasts
    Colston, JT
    de la Rosa, SD
    Strader, JR
    Anderson, MA
    Freeman, GL
    [J]. FEBS LETTERS, 2005, 579 (11) : 2533 - 2540