UKE - UCCS - Research Group Molina

Research Group Molina

Name: Prof. Dr. Cristina E. Molina
Clinic/Institute: Institute of Experimental Cardiovascular Research
Email: [email protected]
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 classical electrophysiological and novel imaging techniques, 2) generate 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 PDEs and G-protein coupled receptors 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. The goal is to apply this knowledge to develop new mechanism-based and patient-tailored therapeutic strategies.

Methods
Publications
Recent Funding

Methods
- Cardiomyocytes, neurons 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

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.
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.
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.
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