AG Molina


Name: Prof. Dr. Cristina E. Molina
Clinic/Institute: Institute of Experimental Cardiovascular Research
Email: c.molina@uke.de
Phone: +49 (0) 40 7410 - 57095

Research Focus and Main research questions

We focus on understanding the basic cellular pathomechanisms underlying cardiac diseases, with special attention on cardiac arrhythmias. In particular, we are interested in cyclic nucleotides signaling in human myocytes and how the remodeling on cAMP/cGMP-dependent kinases (such as PKA, and CaMKII via Epac) signaling is linked to compartment-specific changes in Ca2+-handling. Although many studies have been performed in animal models, the role of cyclic nucleotides, PKA, CaMKII and PDEs in human remains rather unexplored and controversial. We developed a novel isolation method, which allows us to culture human myocytes, to: 1) perform in classical electrophysiological and novel imaging techniques, 2) generate with knock-in /-out models directly in human cells, as new alternative method to animal testing and highly translational model for heart diseases.


Research Projects

  • Role of PDE8 in cAMP dynamics and Ca2+-handling in atrial fibrillation
  • Epac microdomain regulation of Ca2+-handling via cAMP and CaMKII in atrial fibrillation
  • Regional specific remodeling of cGMP pathway in human atrial fibrillation

Our aim is to clarify how specific molecular alterations in cardiac cells and disease-related remodeling cause electrical instability and generate arrhythmias and to apply this knowledge to develop new mechanism-based and patient-tailored therapeutic strategies. Furthermore, our group has the overall responsibility for the translation to human of the animal studies performed at the Institute of Experimental Cardiovascular Research.

  • Methods
  • Methods

    Methods:

    • Cardiomyocytes and fibroblasts isolation
    • Primary cell cultures, including human cells
    • Förster resonance energy transfer (FRET)
    • Patch-clamp
      Measurement of ion currents in isolated cardiomyocytes
    • Measurement of action potentials
    • Contraction measurements in isolated cardiomyocytes
    • Confocal calcium imaging
    • Immunostaining and confocal microscopy
    • Proximity ligation assays (PLA)
    • qPCR

  • Publications:

    Pabel S, Knierim M, Stehle T, Alebrand F, Paulus M, Sieme M, Herwig M, Barsch F, Körtl T, Pöppl A, Wenner B, Ljubojevic-Holzer S, Molina CE, Dybkova N, Camboni D, Fischer TH, Sedej S, Scherr D, Schmid C, Brochhausen C, Hasenfuß G, Maier LS, Hamdani N, Streckfuss-Bömeke K, Sossalla S. Effects of Atrial Fibrillation on the Human Ventricle. Circ Res. 2022 Apr;130(7):994-1010. doi: 10.1161/CIRCRESAHA.121.319718.

    Beneke K, Molina CE. Live Cell Imaging of Cyclic Nucleotides in Human Cardiomyocytes. Methods Mol Biol. 2022;2483:195-204. doi: 10.1007/978-1-0716-2245-2_12.

    Heijman J, Zhou X, Morotti S, Molina CE, Abu-Taha IH, Tekook M, Jespersen T, Zhang Y, Dobrev S, Milting H, Gummert J, Karck M, Kamler M, El-Armouche A, Saljic A, Grandi E, Nattel S, Dobrev D. Enhanced Ca2+-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation. Circ Res. 2023 Apr 28;132(9):e116-e133. doi: 10.1161/CIRCRESAHA.122.321858.

    Grammatika Pavlidou N, Dobrev S, Beneke K, Reinhardt F, Pecha S, Jacquet E, Abu-Taha IH, Schmidt C, Voigt N, Kamler M, Schnabel RB, Baczkó I, Garnier A, Reichenspurner H, Nikolaev VO, Dobrev D, Molina CE. Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism. Eur Heart J. 2023 Jul 14;44(27):2483-2494. doi: 10.1093/eurheartj/ehad086.

    Reinhardt F*, Beneke K*, Grammatica Pavlidou N, Conradi L, Reichenspurner H, Hove-Madsen L, Molina CE. Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling. Cells 2021 10(11), 3042. doi: 10.3390/cells10113042

    Bork NI, Kuret A, Cruz Santos M, Molina CE, Reiterd B, Reichenspurner R, Friebee A, Skryabinf BV, Rozhdestvenskyf TS, Kuhne M,Lukowskic R, Nikolaev NO. Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia. Redox Biol. 2021 Nov 6;48:102179. doi: 10.1016/j.redox.2021.102179. Online ahead of print. PMID: 34763298

    Odening KE, Gomez AM, Dobrev D, Fabritz L, Heinzel FR, Mangoni ME, Molina CE, Sacconi L, Smith G, Milan Stengl, Thomas D, Zaza A, Remme CA, Heijman J. ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research. Europace 2021 Nov 8;23(11):1795-1814. doi: 10.1093/europace/euab142.. doi: 10.1093/europace/euab142. PMID: 34313298

    Berisha F, Götz KR, Wegener JW, Brandenburg S, Subramanian H, Molina CE, Rüffer A, Petersen J, Bernhardt A, Girdauskas E, Jungen C, Pape U, Kraft AE, Warnke S, Lindner D, Westermann D, Blankenberg S, Meyer C, Hasenfuß G, Lehnart SE, Nikolaev VO. cAMP Imaging at Ryanodine Receptors Reveals β2-Adrenoceptor Driven Arrhythmias. Circ Res. 2021 Jun 25;129(1):81-94. doi: 10.1161/CIRCRESAHA.120.318234. Epub 2021 Apr 27. PMID: 33902292

    Beneke K, Molina CE. Molecular Basis of Atrial Fibrillation Initiation and Maintenance. Hearts 2021 2(1), 170-187. doi: 10.3390/hearts2010014

    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. 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

    Heijman J, Muna AP, Veleva T, Molina CE, Sutanto H, Tekook M, Wang Q, Abu-Taha IH, Gorka M, Künzel S, El-Armouche A, Reichenspurner H, Kamler M, Nikolaev VO, Ravens U, Li N, Nattel S, Wehrens XHT, Dobrev D. Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation. Circ Res (2020) Sep 25;127(8):1036-1055. doi: 10.1161/CIRCRESAHA.120.316710. Epub 2020 Jul 30. PMID: 32762493

    Hofhuis J, Bersch K, Wagner S, Molina CE, Fakuade FE, Iyer LM, Streckfuss-Bömeke K, Toischer K, Zelarayán LC, Voigt N, Nikolaev VO, Maier LS, Klinge L, Thoms S. Dysferlin links excitation–contraction coupling to structure and maintenance of the cardiac transverse–axial tubule system. Europace (2020) Jul 1;22(7):1119-1131. doi: 10.1093/europace/euaa093. PMID: 32572487

    Bork NI, Molina CE, Nikolaev VO. cGMP signalling in cardiomyocyte microdomains. Biochem Soc Trans. (2019) Oct 31;47(5):1327-1339. doi: 10.1042/BST20190225. PMID: 31652306

    Molina CE*, Abu-Taha I*, Wang Q, Roselló-Díez E, Kamler M, Ravens U, Wehrens XHT, Hove-Madsen L, Heijman J, Dobrev D. Structural, electrical and calcium-handling remodeling of the atria in heart failure patients with and without atrial fibrillation. Frontiers in Physiol., section Cardiac Electrophysiology (2018) Oct. 9. doi: PMID:

    Ahmad S, Tirilomis P, Pabel S, Dybkova N, Hartmann N, Molina CE, Tirilomis T, Kutschka I, Frey N, Maier LS, Hasenfuss G, Streckfuss-Bömeke K, Sossalla S. The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy. ESC Heart Fail. (2019) Feb;6(1):154-163. doi: 10.1002/ehf2.12378. Epub 2018 Oct 30. PMID: 30378291

    Heijman J, Molina CE, Voigt N. Book chapter: Voltage-Gated Calcium Channels and Their Roles in Cardiac Electrophysiology. Channelopathies in Heart Disease (2018) 187, 77-94 Springer Verlag.

    Molina CE, Abu-Taha IH, Wang Q, Roselló-Díez E, Kamler M, Nattel S, Ravens U, Wehrens XHT, Hove-Madsen L, Heijman J, Dobrev D. Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation. Front Physiol. (2018) Oct 9;9:1383. doi: 10.3389/fphys.2018.01383. eCollection 2018. PMID: 30356673

    Molina CE, Jacquet E, Ponien P, Muñoz-Guijosa C, Baczkó I, Maier LS, Donzeau-Gouge P, Dobrev D, Fischmeister R, Garnier A. Identification of optimal reference genes for transcriptomic analyses in normal and diseased human heart. Cardiovasc Res. (2018) Feb 1;114(2):247-258. doi: 10.1093/cvr/cvx182. PMID: 29036603

    Molina CE, Llach A, Herraiz-Martínez A, Tarifa C, Barriga M, Wiegerinck RF, Fernandes J, Cabello N, Vallmitjana A, Benitez R, Montiel J, Cinca J, Hove-Madsen L. Prevention of adenosine A2A receptor activation diminish beat-to-beat alternation in human atrial myocytes. Basic Res Cardiol. (2016) Jan;111(1):5. doi: 10.1007/s00395-015-0525-2. Epub 2015 Nov 26. PMID: 26611209

    Molina CE*, Johnson D*, Mehel H, Spätjens R, Mika D, Haj Slimane Z, Algalarrondo V, Leroy J, Abi-Gerges N, Volders P, Fischmeister R, Vandecasteele G. Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases. J Am Heart Assoc. (2014) Jun 5;3(3):e000858. doi: 10.1161/JAHA.114.000858. PMID: 24904016

    Molina CE*, Leroy J*, Richter W, Xie M, Scheitrum C, Lee I, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R. Phosphodiesterase-4 Controls Cyclic AMP/PKA-Dependent Signaling in Human Atrium and Protects against Atrial Fibrillation. J Am Coll Cardiol. (2012) Jun 12;59(24):2182-90. doi: 10.1016/j.jacc.2012.01.060. PMID: 22676938

    Molina CE*, Llach A*, Prat-Vidal C, Fernandes J, Casadó V, Ciruela F, Lluis C, Franco R, Cinca J, Hove-Madsen L. Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors. Eur Heart J (2011) Mar;32(6):721-9. doi: 10.1093/eurheartj/ehq464. Epub 2010 Dec 22. PMID: 21177700

  • Recent Funding:

    Prof. Molina is funded by the Gertraud and Heinz Rose Foundation.

    2023-2027:
    Second messenger nanodomains in human atrial myocytes: from local signalling regulation to personalized therapeutic approaches | DFG | Heisenberg grant

    2022-2025:
    Mapping cAMP nanodomains in human atrial myocytes and their dysregulation in atrial fibrillation | DFG | 358’125 CHF

    2019-2022:
    Role of PDE8 in cAMP dynamic and calcium signaling in atrial fibrillation | DFG | 494’200 CHF

    2019-2020:
    Role of atrial metabolism dysfunction and cAMP remodeling in arrhythmogenesis in type 2 diabetes | DZHK Share Expertise | 43’156 CHF

    2013-2014:
    Effects of atrial fibrillation on the distribution and frequency of spontaneous calcium release events in human atrial myocytes | Marie Curie Actions (PIEF)– European Commission| 166’336 CHF

    2011-2012:
    Role of PDE4 on cAMP dynamics and calcium handling in atrial fibrillation | Institut de France | 104’000 CHF