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NADPH oxidases in cardiac metabolic remodeling


The project objective is to study the role of NADPH oxidases in cardiac metabolic remodeling in response to various stressors. NADPH oxidases (NOXs) are a family of enzymes that generate reactive oxygen species (ROS) together with several other sources of ROS in the heart. Oxidative stress and redox signaling are important factors in the cardiac response to acute and sustained stress. In collaboration with the King's British Heart Foundation (BHF) Centre of Research Excellence, the cardiovascular research group (CVRG) at the Department of Medical Biology (IMB) has investigated the role of NOXs in cardiac metabolic remodeling.

The project has shown that NADPH oxidases is important in cardiac metabolic remodeling in response to various stressors, including obesity, hypertension, and diabetes, but also due to physiological stress such as exercise. In total CVRG has received funding for this project from several external sources such as Norwegian Health association and the NOVO Nordic foundation. This collaboration has contributed to sustained exchange of scientific personnel between the groups, from research line students, PhD students, post-docs, but also junior faculty members and professors. The project has led to 9 publications in high impact international journals, including 2 reviews and 7 original scientific papers. There is currently also one submitted original scientific paper and one ongoing study at the UiT.

Publications

  1. Hansen SS, Pedersen TM, Marin J, Boardman NT, Shah AM, Aasum E, Hafstad AD. Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling. Antioxidants (Basel). 2022 Jan 10;11(1):143. doi: 10.3390/antiox11010143. PMID: 35052647; PMCID: PMC8772838.
  2. Hafstad AD, Hansen SS, Lund J, Santos CXC, Boardman NT, Shah AM, Aasum E. NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity. Antioxidants (Basel). 2020 Feb 19;9(2):171. doi: 10.3390/antiox9020171. PMID: 32093119; PMCID: PMC7070669.
  3. Hansen SS, Aasum E, Hafstad AD. The role of NADPH oxidases in diabetic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt B):1908-1913. doi: 10.1016/j.bbadis.2017.07.025. Epub 2017 Jul 25. PMID: 28754449.
  4. Hancock M, Hafstad AD, Nabeebaccus AA, Catibog N, Logan A, Smyrnias I, Hansen SS, Lanner J, Schröder K, Murphy MP, Shah AM, Zhang M. Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise. Elife. 2018 Dec 27;7:e41044. doi: 10.7554/eLife.41044. PMID: 30589411; PMCID: PMC6307857.
  5. Beretta M, Santos CX, Molenaar C, Hafstad AD, Miller CC, Revazian A, Betteridge K, Schröder K, Streckfuß-Bömeke K, Doroshow JH, Fleck RA, Su TP, Belousov VV, Parsons M, Shah AM. Nox4 regulates InsP3receptor-dependent Ca2+release into mitochondria to promote cell survival. EMBO J. 2020 Oct 1;39(19):e103530. doi: 10.15252/embj.2019103530. Epub 2020 Aug 10. PMID: 33001475; PMCID: PMC7527947.
  6. Nabeebaccus AA, Zoccarato A, Hafstad AD, Santos CX, Aasum E, Brewer AC, Zhang M, Beretta M, Yin X, West JA, Schröder K, Griffin JL, Eykyn TR, Abel ED, Mayr M, Shah AM. Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation. JCI Insight. 2017 Dec 21;2(24):e96184. doi: 10.1172/jci.insight.96184. PMID: 29263294; PMCID: PMC5752273.
  7. Santos CX, Hafstad AD, Beretta M, Zhang M, Molenaar C, Kopec J, Fotinou D, Murray TV, Cobb AM, Martin D, Zeh Silva M, Anilkumar N, Schröder K, Shanahan CM, Brewer AC, Brandes RP, Blanc E, Parsons M, Belousov V, Cammack R, Hider RC, Steiner RA, Shah AM. Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling. EMBO J. 2016 Feb 1;35(3):319-34. doi: 10.15252/embj.201592394. Epub 2016 Jan 7. PMID: 26742780; PMCID: PMC4741303.
  8. Nabeebaccus A, Hafstad A, Eykyn T, Yin X, Brewer A, Zhang M, Mayr M, Shah A. Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart. Lancet. 2015 Feb 26;385 Suppl 1:S73. doi: 10.1016/S0140-6736(15)60388-9. PMID: 26312895.
  9. Hafstad AD, Nabeebaccus AA, Shah AM. Novel aspects of ROS signalling in heart failure. Basic Res Cardiol. 2013 Jul;108(4):359. doi: 10.1007/s00395-013-0359-8. Epub 2013 Jun 6. PMID: 23740217.


Members:

Anne Dragøy Hafstad (Principal investigator)
Trine Lund
Neoma Tove Boardman
Ellen Aasum


Financial/grant information:

2012: 3 year fellowship from the Norwegian Health Association

2013: Novo Nordic foundation: Running costs: 400 000 NOK

2014: Novo Nordic foundation: Running costs: 400 000 NOK