AG Nikolaev


Name: Prof. Dr. Viacheslav O. Nikolaev
Clinic/Institute: Institute of Experimental Cardiovascular Research
Email: v.nikolaev@uke.de
Phone: +49 (0) 40 7410 - 57095

Research Focus and Main research questions

The cyclic nucleotides (cAMP and cGMP) regulate cardiac function acting as second messengers for sympathetic and parasympathetic, nitric oxide (NO) and natriuretic peptide systems. Cyclic nucleotides may exert beneficial or deleterious effects on the heart, depending on the duration of the stimulation. Acute elevation of cyclic nucleotides regulates cardiac excitation-contraction coupling. Chronic elevation of cAMP contributes to the development of many cardiac diseases such as cardiac hypertrophy, heart failure and atrial fibrillation, while cGMP seems to covey mostly beneficial effects. The general objective of our laboratory is to understand the molecular mechanisms responsible for the homeostasis of these two second messengers and the functional consequences for cardiac function. By combining biochemical, molecular, genetic, electrophysiological and imaging techniques we aim to elucidate the mechanisms responsible for the temporal and spatial control of cyclic nucleotides signalling and their relevance to both physiological and disease conditions in animal models.

  • Methods
  • Methods

    Methods:

    • Cardiomyocytes isolation
    • Förster resonance energy transfer (FRET) biosensors
    • scanning ion conductance microscopy (SICM)
    • confocal imaging
    • immunostaining
    • western blot
    • qPCR

  • Publications:

    De Jong KA, Nikolaev VO. Multifaceted remodelling of cAMP microdomains driven by different aetiologies of heart failure FEBS J. 2021 Jan 8. doi: 10.1111/febs.15706. Online ahead of print. PMID: 33415835 Review.

    Garnier A, Bork NI, Jacquet E, Zipfel S, Muñoz-Guijosa C, Baczkó I, Reichenspurner H, Donzeau-Gouge P, Maier LS, Dobrev D, Girdauskas E, Nikolaev VO, Fischmeister R, Molina CE. Garnier A, et al. Mapping genetic changes in the cAMP-signaling cascade in human atria. J Mol Cell Cardiol. 2021 Feb 22;155:10-20. doi: 10.1016/j.yjmcc.2021.02.006. Online ahead of print.J Mol Cell Cardiol. 2021. PMID: 33631188

    Iqbal Z, Ismaili D, Dolce B, Petersen J, Reichenspurner H, Hansen A, Kirchhof P, Eschenhagen T, Nikolaev VO, Molina CE, Christ T. Regulation of basal and norepinephrine-induced cAMP and ICa in hiPSC-cardiomyocytes: Effects of culture conditions and comparison to adult human atrial cardiomyocytes. Cell Signal. 2021 Mar 4:109970. doi: 10.1016/j.cellsig.2021.109970. Online ahead of print.Cell Signal. 2021. PMID: 33677066

    Dolce B, Christ T, Grammatika Pavlidou N, Yildirim Y, Reichenspurner H, Eschenhagen T, Nikolaev VO, Kaumann AJ, Molina CE. Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation Naunyn Schmiedebergs Arch Pharmacol. 2021 Feb;394(2):291-298. doi: 10.1007/s00210-020-01968-1. Epub 2020 Sep 19.Naunyn Schmiedebergs Arch Pharmacol. 2021.PMID: 32949251

    Li X, Li J, Martinez EC, Froese A, Passariello CL, Henshaw K, Rusconi F, Li Y, Yu Q, Thakur H, Nikolaev VO, Kapiloff MS. Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy Circulation. 2020 Sep 8;142(10):948-962. PMID: 32611257

    Schobesberger S, Wright PT, Poulet C, Sanchez Alonso Mardones JL, Mansfield C, Friebe A, Harding SE, Balligand JL, Nikolaev VO, Gorelik J. β 3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes Elife. 2020 Mar 31;9:e52221. PMID: 32228862

    Špiranec Spes K, Chen W, Krebes L, Völker K, Abeßer M, Eder Negrin P, Cellini A, Nickel A, Nikolaev VO, Hofmann F, Schuh K, Schweda F, Kuhn M. Heart-Microcirculation Connection: Effects of ANP (Atrial Natriuretic Peptide) on Pericytes Participate in the Acute and Chronic Regulation of Arterial Blood Pressure Hypertension. 2020 Nov;76(5):1637-1648. doi: 10.1161/HYPERTENSIONAHA.120.15772. Epub 2020 Sep 21. PMID:32951468

    Diering S, Stathopoulou K, Goetz M, Rathjens L, Harder S, Piasecki A, Raabe J, Schulz S, Brandt M, Pflaumenbaum J, Fuchs U, Donzelli S, Sadayappan S, Nikolaev VO, Flenner F, Ehler E, Cuello F. Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents J Biol Chem. 2020 Nov 6;295(45):15342-15365. PMID: 32868295

    Eiringhaus J, Wünsche CM, Tirilomis P, Herting J, Bork N, Nikolaev VO, Hasenfuss G, Sossalla S, Fischer TH. Sacubitrilat reduces pro-arrhythmogenic sarcoplasmic reticulum Ca 2+ leak in human ventricular cardiomyocytes of patients with end-stage heart failure ESC Heart Fail. 2020 Oct;7(5):2992-3002. doi: 10.1002/ehf2.12918. PMID: 32710603

    Hofhuis J, Bersch K, Wagner S, Molina C, Fakuade FE, Iyer LM, Streckfuss-Bömeke K, Toischer K, Zelarayán LC, Voigt N, Nikolaev VO, Maier LS, Klinge L, Thoms S.Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy Europace. 2020 Jul 1;22(7):1119-1131. PMID: 32572487

    Bastug-Özel Z, Wright PT, Kraft AE, Pavlovic D, Howie J, Froese A, Fuller W, Gorelik J, Shattock MJ, Nikolaev VO. Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain. Cardiovasc Res. 2019 Mar 1;115(3):546-555.

    Subramanian H, Froese A, Jönsson P, Schmidt H, Gorelik J, Nikolaev VO. Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP. Nat Commun. 2018 Jun 22;9(1):2446.

    Bork NI, Nikolaev VO. cGMP Signaling in the Cardiovascular System-The Role of Compartmentation and Its Live Cell Imaging. Int J Mol Sci. 2018 Mar 10;19(3). pii: E801.

    Pavlaki N, Nikolaev VO. Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes. J Cardiovasc Dev Dis. 2018 Jan 19;5(1). pii: E4.

    Jungen C, Scherschel K, Eickholt C, Kuklik P, Klatt N, Bork N, Salzbrunn T, Alken F, Angendohr S, Klene C, Mester J, Klöcker N, Veldkamp MW, Schumacher U, Willems S, Nikolaev VO, Meyer C. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias. Nat Commun. 2017 Jan 27;8:14155. doi: 10.1038/ncomms14155.

    Kraft AE, Nikolaev VO. FRET Microscopy for Real-Time Visualization of Second Messengers in Living Cells. Methods Mol Biol. 2017;1563:85-90.

    Froese A, Nikolaev VO. Imaging alterations of cardiomyocyte cAMP microdomains in disease. Front Pharmacol. 2015 Aug 25;6:172.

    Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Maier LS, Hasenfuss G, Nikolaev VO. In vivo model with targeted cAMP biosensor reveals changes in receptor-microdomain communication in cardiac disease. Nat Commun. 2015 Apr 28;6:6965.

    Perera RK, Sprenger JU, Steinbrecher JH, Hübscher D, Lehnart SE, Abesser M, Schuh K, El-Armouche A, Nikolaev VO. Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res. 2015 Apr 10;116(8):1304-11.

    Götz KR, Sprenger JU, Perera RK, Steinbrecher JH, Lehnart SE, Kuhn M, Gorelik J, Balligand JL, Nikolaev VO. Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes. Circ Res. 2014 Apr 11;114(8):1235-45.

    Froese A, Breher SS, Waldeyer C, Schindler RF, Nikolaev VO, Rinné S, Wischmeyer E, Schlueter J, Becher J, Simrick S, Vauti F, Kuhtz J, Meister P, Kreissl S, Torlopp A, Liebig SK, Laakmann S, Müller TD, Neumann J, Stieber J, Ludwig A, Maier SK, Decher N, Arnold HH, Kirchhof P, Fabritz L, Brand T. Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest. 2012 Mar;122(3):1119-30.

    Börner S, Schwede F, Schlipp A, Berisha F, Calebiro D, Lohse MJ, Nikolaev VO. FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells. Nat Protoc. 2011 Apr;6(4):427-38.

    Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010 Mar 26;327(5973):1653-7.

    Nikolaev VO, Gambaryan S, Lohse MJ. Fluorescent sensors for rapid monitoring of intracellular cGMP. Nat Methods. 2006 Jan;3(1):23-5.

  • Recent Funding:

    Prof. Nikolaev and the Institute of Experimental Cardiovascular Research are funded by the Gertraud and Heinz Rose Foundation and several national and international grants.

    Our institute participates in the DFG research group 2060 “cGMP in cell growth and survival” with a subproject "cGMP microdomains in cardiomyocyte hypertrophy and heart failure". Moreover, we have subprojects in the newly funded Collaborative Research Center SFB1328 “Adenine nucleotides in immunity and inflammation” as well as in the European Research Area (ERANet) program called ERA-CVD.

    As part of the DZHK Hamburg/Kiel/Lübeck partner site, a scientific project entitled "Modulation of cAMP microdomains" is being purused. Its goal is the preclinical development of new therapeutic approached in the field of specific modulation of subcellular cAMP signals.

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