Cytochrome P450-dependent eicosanoids in sex-specific mechanisms of cardiac hypertrophy and arrhythmia

• Applicant: Dr. Wolf-Hagen Schunck
• Subject Area: Nephrology
• Term: from 2008 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 60843499

• Final Report Year: 2017

Final Report Abstract

This project aimed at understanding the role of cytochrome P450 (CYP)-dependent eicosanoids in the sex-specific development of cardiac hypertrophy and heart failure. To modulate CYP-eicosanoid formation under in vivo conditions, transgenic mouse models with cardiomyocyte-specific overexpression of CYP2J2 (the major CYP epoxygenase in the human heart) or Cyp4a12a (major CYP ω- hydroxylase in male mice) were used. We found that eicosanoids generated via the CYP epoxygenase as well as CYP hydroxylase pathway interfere in a sex-specific manner with the development of chronic pressure overload-induced maladaptive cardiac hypertrophy. While wildtype females showed already some degree of intrinsic protection, males clearly benefited from transgenic CYP2J2 overexpression as reflected by largely reduced mortality and cardiac arrhythmia susceptibility. Searching for the identity of cardioprotective metabolites generated by CYP2J2, we identified omega-3 epoxyeicosanoids, such as 17,18-EEQ (17,18-epoxyeicosatetraenic acid), as highly potent cardioprotective lipid mediators. Cyp4a12- overexpression increased cardiac 20-HETE (20-hydroxyeicosatetraenoic acid) formation and significantly accelerated the development of dilative cardiomyopathy upon chronic pressure overload. This detrimental effect was more pronounced in male compared to female mice. In conclusion, these data indicate that the balance between 20-HETE and epoxyeicosanoids may play an important role in the sex- specific development of cardiac disease. Based on the cardioprotective lipid mediators generated by CYP epoxygenases, the applicants founded a start-up company (OMEICOS Therapeutics) that is now developing epoxyeicosanoid-like drug candidates for the treatment of cardiac arrhythmia.

Publications

• Arachidonic acid-metabolizing cytochrome p450 enzymes are targets of omega-3 fatty acids. J Biol Chem. 2010;285:32720-31733
  Arnold C, Markovic M, Blossey K, Wallukat G, Fischer R, Dechend R, Konkel A, von Schacky C, Luft FC, Muller DN, Rothe M, Schunck WH
  
• Eicosanoid Derivatives. WO 2010/081683
  Schunck Wolf-Hagen; Wallukat Gerd; Fischer Robert; Arnold Cosima; Mueller Dominik N; Puli Narender; Falck John R
  
• 17(r),18(s)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (epa) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analogues. J Med Chem. 2011;54:4109-4118
  Falck JR, Wallukat G, Puli N, Goli M, Arnold C, Konkel A, Rothe M, Fischer R, Muller DN, Schunck WH
  
• Cyp-eicosanoids - a new link between omega-3 fatty acids and cardiac disease? Prostaglandins Other Lipid Mediat. 2011;96:99-108
  Westphal C, Konkel A, Schunck WH
  
• Role of cytochrome p450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta. 2011;1814:210-222
  Konkel A, Schunck WH
  
• Cyp2j2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy. PLoS One. 2013;8:e73490
  Westphal C, Spallek B, Konkel A, Marko L, Qadri F, Degraff LM, Schubert C, Bradbury JA, Regitz-Zagrosek V, Falck JR, Zeldin DC, Muller DN, Schunck WH, Fischer R
  
• Sodium Chloride Drives Experimental Autoimmune Disease by the Induction of Pathogenic Th17 Cells. Nature 2013; 496(7446):518-22
  Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Linker RA, Muller DN, Hafler DA
  
• Cyp-13a12 of the nematode c. Elegans is a pufa-epoxygenase involved in behavioural response to reoxygenation. Biochem J. 2014;464:61-71
  Keller J, Ellieva A, Ma DK, Ju J, Nehk E, Konkel A, Falck JR, Schunck WH, Menzel R
  
• Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the cyp-epoxygenase pathway. J Lipid Res. 2014;55:1150-1164
  Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH
  
• Cytochrome p450 enzymes in the bioactivation of polyunsaturated fatty acids and their role in cardiovascular disease. Advances in experimental medicine and biology. 2015;851:151-187
  Westphal C, Konkel A, Schunck WH
  
• High salt reduces the activation of IL-4 and IL-13 stimulated macrophages. J Clin Invest. 2015, 125: 4223-38
  Binger KJ, Gebhardt M, Heinig M, Rintisch C, Schroeder A, Neuhofer W, Hilgers K, Manzel A, Schwartz C, Kleinewietfeld M, Voelkl J, Schatz V, Linker RA, Lang F, Voehringer D, Wright MD, Hubner N, Dechend R, Jantsch J, Titze J, Muller DN
  
• New role for the (pro)renin receptor in T-cell development. Blood 2015;126(4):504-7
  Geisberger S, Maschke U, Gebhardt M, Kleinewietfeld M, Manzel A, Linker RA, Chidgey A, Dechend R, Nguyen G, Daumke O, Muller DN, Wright MD*, Binger KJ