Redox Signaling // Science

Reactive oxygen and nitrogen species (ROS and RNS) and products from their reactions with cellular macromolecules play a significant role in the development of cardiovascular diseases and cancer. Cells have developed intricate mechanisms by which they respond to ROS and RNS, thereby balancing their effects in cells and tissues. The protective effects are mediated by transcriptional responses to restore cellular homeostasis. The key mediator of cellular protection against ROS and RNS is transcription factor Nrf2, which regulates the expression of numerous protective genes.

Traditionally, Nrf2 has been considered to be beneficial and to protect against many diseases, which has motivated the development of Nrf2 activating drugs for e.g. chemoprevention of intestinal tumors and lung cancer. However, the levels of Nrf2 are often elevated in cancer increasing the cancer cell survival and causing resistance to chemotherapy. The role of Nrf2 in cardiovascular diseases is also controversial, as Nrf2 has been shown to have protective effects in the vasculature, whereas it may have unfavorable systemic metabolic effects that may counteract its local beneficial effects.

The main goal of our group is to elucidate the role of Nrf2 in cardiovascular diseases and cancer, in order to find new targets for the prevention and treatment of these diseases.

Major research topics

  • The role of Nrf2 in vascular inflammation, lipoprotein metabolism and cardiovascular diseases.
  • The role of Nrf2 in non-alcoholic fatty liver disease and hepatosteatosis.
  • The mechanisms and consequences of Nrf2 dysregulation in cancer, and the use of Nrf2 as a pharmacological target for cancer therapy.
  • Identification of new Nrf2 target genes, with a special emphasis on microRNAs involved in cardiovascular diseases and cancer.

Research methods

State-of-the-art biochemical, molecular and cell biological techniques, including Next Generation Sequencing techniques (GRO-seq, RNA-seq, miRNA-seq, DNAse-seq and ChIP-seq), cloning and vector development, adeno- and lentiviral technology, RNA-interference techniques and microRNA techniques, as well as mouse models, imaging techniques (MRI, ultrasound), small surgery, Isolation of primary cells and histopathology.

Funding sources

The Academy of Finland, The Jane and Aatos Erkko Foundation, Finnish Cancer Foundation, Competitive Research Funding of the Northern Savo Hospital District special state subsidy for health research (KUH VTR-funding).

Collaborations

Dr. Bruce A. Freeman, University of Pittsburgh, USA, Dr. Masayuki Yamamoto, Tohoku School of Medicine, Sendai, Japan, Dr. Matti Jauhiainen, University of Helsinki, Dr. Eija Pirinen, University of Helsinki, Dr. Lea Sistonen, Åbo Academi University, Dr. Jorma Palvimo, University of Eastern Finland, Dr. Jari Koistinaho, University of Eastern Finland, Dr. Kai Kaarniranta, University of Eastern Finland.

Selected publications

  1. Kuosmanen, S.M., Viitala, S., Laitinen, T., Peräkylä, M., Pölönen, P., Kansanen, E., Leinonen, H., Raju, S., Wienecke-Baldacchino, A. Närvänen, A., Poso, A., Heinäniemi, M., Heikkinen, S., Levonen, A.-L. The Effects of Sequence Variation on Genome-wide NRF2 Binding - New Target Genes and Regulatory SNPs. Nucleic Acids Res. 44:1760-1775, 2016.
  2. Leinonen, H.M., Kansanen, E., Pölönen, P., Heinäniemi, M., Levonen, A.-L. Role of the Keap1-Nrf2 Pathway in Cancer. Adv. Cancer Res. 122: 281-320, 2014.
  3. Ruotsalainen, A.-K., Inkala, M., Partanen, M.E., Lappalainen, J.P., Kansanen, E., Mäkinen, P.I., Heinonen, S.E., Laitinen, H.M., Heikkilä, J., Vatanen, T., Hörkkö, S., Yamamoto, M., Ylä-Herttuala, S., Jauhiainen, M., Levonen, A.-L. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc. Res. 98:107-115, 2013.
  4. Leinonen, H.M., Ruotsalainen, A.-K., Määttä, A.M., Laitinen, H.M., Kuosmanen, S.M., Kansanen, E., Pikkarainen, J.T., Lappalainen, J.P., Samaranayake, H., Lesch, H.P., Kaikkonen, M.U., Ylä-Herttuala, S., Levonen, A.-L. Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. Cancer Res. 72:6227-6235, 2012. 
  5. Kansanen, E., Bonacci, G., Schopfer, F.J., Linna, S., Tong, K.I., Leinonen, H., Woodcock, S.R., Yamamoto, M., Carlberg, C., Ylä-Herttuala, S., Freeman, B.A., Levonen, A.-L. Electrophilic nitro-fatty acids activate Nrf2 by a Keap1 cysteine 151-independent mechanism. J. Biol. Chem. 286:14019-14027, 2011.
  6. Kansanen, E., Jyrkkänen, H.K., Volger O.L., Leinonen, H., Kivelä, A.M., Häkkinen, S.-K., Woodcock, S.R., Schopfer, F.J., Horrevoets, A.J, Ylä-Herttuala, S., Freeman, B.A., Levonen, A.-L. Nrf2-dependent and independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as a major pathway activated by nitro-oleic acid. J. Biol. Chem. 284:33233-33241, 2009.
  7. Jyrkkänen, H.-K., Kansanen, E., Inkala, M., Kivelä, A.M., Hurttila, H., Heinonen, S.E., Goldsteins, G., Jauhiainen, S., Tiainen, S., Makkonen, H., Oskolkova, O., Afonyushkin, T., Koistinaho, J.,  Yamamoto, M., Bochkov, V.N., Ylä-Herttuala, S., Levonen, A.-L. Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circ. Res. 103: e1-9, 2008.
  8. Levonen, A.-L, Vähäkangas, E., Koponen, J.K., Ylä-Herttuala, S. Antioxidant gene therapy for cardiovascular disease: current status and future perspectives. Circulation 117: 2142-2150, 2008
  9. Levonen, A.L, Landar, A., Ramachandran, A., Ceaser, E.K., Dickinson, D.A., Zanoni, G., Morrow, J.D., and Darley-Usmar, V.M. Cellular mechanisms of redox cell signaling: the role of cysteine modification in controlling antioxidant defenses in response to electrophilic lipid oxidation products. Biochem. J. 378: 373-382, 2004.
  10. Levonen, A.-L., Inkala, M., Heikura, T., Jauhiainen, S., Jyrkkänen, H.-K., Kansanen, E., Määttä, K., Romppanen, E., Turunen, P., Rutanen, J., and Ylä-Herttuala, S. Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler. Thromb. Vasc. Biol. 27: 741-747, 2007.