Lise Román Moltzau

• Andresen, Henriette; Pérez-Ternero, Cristina; Robinson, Jerid; Dickey, Deborah M.; Hobbs, Adrian J. & Potter, Lincoln R. [Show all 9 contributors for this article] (2023). Novel enhancers of guanylyl cyclase-A activity acting via allosteric modulation. British Journal of Pharmacology. ISSN 0007-1188. doi: 10.1111/bph.16203. Full text in Research Archive Show summary

  Abstract Background and Purpose Guanylyl cyclase‐A (GC‐A), activated by endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), plays an important role in the regulation of cardiovascular and renal homeostasis and is an attractive drug target. Even though small molecule modulators allow oral administration and longer half‐life, drug targeting of GC‐A has so far been limited to peptides. Thus, in this study we aimed to develop small molecular activators of GC‐A. Experimental Approach Hits were identified through high‐throughput screening and optimized by in silico design. Cyclic GMP was measured in QBIHEK293A cells expressing GC‐A, GC‐B or chimerae of the two receptors using AlphaScreen technology. Binding assays were performed in membrane preparations or whole cells using 125 I‐ANP. Vasorelaxation was measured in aortic rings isolated from Wistar rats. Key Results We have identified small molecular allosteric enhancers of GC‐A, which enhanced ANP or BNP effects in cellular systems and ANP‐induced vasorelaxation in rat aortic rings. The mechanism of action appears novel and not mediated through previously described allosteric binding sites. In addition, the selectivity and activity depend on a single amino acid residue that differs between the two similar receptors GC‐A and GC‐B. Conclusion and Implications We describe a novel allosteric binding site on GC‐A, which can be targeted by small molecules to enhance ANP and BNP effects. These compounds will be valuable tools in further development and proof‐of‐concept of GC‐A enhancement for the potential use in cardiovascular therapy.

• Calamera, Gaia; Moltzau, Lise Roman; Levy, Finn Olav & Andressen, Kjetil Wessel (2022). Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts. International Journal of Molecular Sciences. ISSN 1661-6596. 23:2145(4), p. 1–24. doi: 10.3390/ijms23042145. Full text in Research Archive Show summary

  Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.

• Manfra, Ornella; Calamera, Gaia; Froese, Alexander; Arunthavarajah, Dulasi; Surdo, Nicoletta C. & Meier, Silja [Show all 14 contributors for this article] (2022). CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors. Cardiovascular Research (CVR). ISSN 0008-6363. 118(6), p. 1506–1519. doi: 10.1093/cvr/cvab167. Full text in Research Archive Show summary

  Abstract Aims Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signalling in adult cardiomyocytes. Methods and results We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crest increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. Conclusion These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP, is able to induce lusitropic and negative inotropic responses.

• Calamera, Gaia; Li, Dan; Ulsund, Andrea Hembre; Kim, Jeong Joo; Neely, Oliver C. & Moltzau, Lise Roman [Show all 11 contributors for this article] (2019). FRET-based cyclic GMP biosensors measure low cGMP concentrations in cardiomyocytes and neurons. Communications Biology. 2:394, p. 1–12. doi: 10.1038/s42003-019-0641-x. Full text in Research Archive Show summary

  Several FRET (fluorescence resonance energy transfer)-based biosensors for intracellular detection of cyclic nucleotides have been designed in the past decade. However, few such biosensors are available for cGMP, and even fewer that detect low nanomolar cGMP concentrations. Our aim was to develop a FRET-based cGMP biosensor with high affinity for cGMP as a tool for intracellular signaling studies. We used the carboxyl-terminal cyclic nucleotide binding domain of Plasmodium falciparum cGMP-dependent protein kinase (PKG) flanked by different FRET pairs to generate two cGMP biosensors (Yellow PfPKG and Red PfPKG). Here, we report that these cGMP biosensors display high affinity for cGMP (EC50 of 23 ± 3 nM) and detect cGMP produced through soluble guanylyl cyclase and guanylyl cyclase A in stellate ganglion neurons and guanylyl cyclase B in cardiomyocytes. These biosensors are therefore optimal tools for real-time measurements of low concentrations of cGMP in living cells.

• Cosson, Marie-Victoire; Hiis, Halvard Gautefall; Moltzau, Lise Roman; Levy, Finn Olav & Krobert, Kurt Allen (2019). Knockout of adenylyl cyclase isoform 5 or 6 differentially modifies the ? <sub>1</sub> -adrenoceptor-mediated inotropic response. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 131, p. 132–145. doi: 10.1016/j.yjmcc.2019.04.017. Full text in Research Archive
• Moltzau, Lise Roman; Meier, Silja; Andressen, Kjetil Wessel & Levy, Finn Olav (2017). Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy. In Nikolaev, Viacheslav & Zaccolo, Manuela (Ed.), Microdomains in the Cardiovascular System.. Springer. ISSN 9783319545783. p. 245–271. doi: 10.1007/978-3-319-54579-0_12. Full text in Research Archive
• Meier, Silja; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Hougen, Karina & Skomedal, Tor [Show all 10 contributors for this article] (2017). PDE3 inhibition by C-type natriuretic peptide-induced cGMP enhances cAMP-mediated signaling in both non-failing and failing hearts. European Journal of Pharmacology. ISSN 0014-2999. 812, p. 174–183. doi: 10.1016/j.ejphar.2017.07.014. Full text in Research Archive
• Ahamed, Muneer; Vermeulen, Koen; Schnekenburger, Michael; Moltzau, Lise Roman; Levy, Finn Olav & Marton, Janos [Show all 10 contributors for this article] (2017). Synthesis, Enzyme Assays and Molecular Docking Studies of Fluorinated Bioisosteres of Santacruzamate A as Potential HDAC Tracers. Letters in Drug Design & Discovery. ISSN 1570-1808. 14(7), p. 787–797. doi: 10.2174/1570180813666161101152943. Full text in Research Archive Show summary

  Histone deacetylases (HDACs) emerged as important epigenetic regulators of gene expression. In order to identify potential positron emission tomography (PET) tracers for imaging HDACs, we evaluated in vitro and in cellulo activities of some compounds that were reported as potent HDAC2-selective inhibitors. We observed marked differences between reported activity values and the values obtained in our assays for some of the compounds. To understand the structural basis of the activity of some of these inhibitors, we also performed molecular docking studies to understand their interaction patterns and binding modes with HDAC2. We observed the low affinity compounds 4, 6 and 7 did not showed equal number of key π-π interactions and hydrogen bonding when compared to high affinity compounds, and could be the possible reason for poor inhibition as reflected in in vitro assays. These preliminary experimental and computational results will help to interpret the HDAC affinity values of these key compounds with caution.

• Eikemo, Hilde; Moltzau, Lise Roman; Nguyen, Hong Cam Thi; Levy, Finn Olav; Skomedal, Tor & Osnes, Jan-Bjørn (2016). CaMKII and at least two unidentified kinases phosphorylate regulatory light chain in non-contracting cardiomyocytes. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 477(1), p. 14–19. doi: 10.1016/j.bbrc.2016.05.138. Full text in Research Archive
• Eikemo, Hilde; Moltzau, Lise Roman; Hussain, Rizwan; Nguyen, Hong Cam Thi; Qvigstad, Eirik & Skomedal, Tor [Show all 8 contributors for this article] (2016). CaMKII in addition to MLCK contributes to phosphorylation of regulatory light chain in cardiomyocytes. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 471(1), p. 219–225. doi: 10.1016/j.bbrc.2016.01.132. Full text in Research Archive
• Moltzau, Lise Roman; Meier, Silja; Aronsen, Jan Magnus; Afzal, Faraz; Sjaastad, Ivar & Skomedal, Tor [Show all 9 contributors for this article] (2014). Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium. Naunyn-Schmiedeberg's Archives of Pharmacology. ISSN 0028-1298. 387(5), p. 407–417. doi: 10.1007/s00210-013-0953-1. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Skogestad, Jonas; Ørstavik, Øivind & Lothe, Gustav B [Show all 11 contributors for this article] (2014). Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle. Journal of Pharmacology and Experimental Therapeutics. ISSN 0022-3565. doi: 10.1124/jpet.114.214882. Full text in Research Archive
• Brudeli, Bjarne; Navaratnarajah, Mirusha; Andressen, Kjetil Wessel; Manfra, Ornella; Moltzau, Lise Roman & Nilsen, Nils Olav [Show all 8 contributors for this article] (2014). Discovery and pharmacological profile of new hydrophilic 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry Letters. ISSN 0960-894X. 24(18), p. 4598–4602. doi: 10.1016/j.bmcl.2014.06.083. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Nguyen, Hong Cam Thi; Hougen, Karina & Ørstavik, Øivind [Show all 12 contributors for this article] (2013). SERCA2 activity is involved in the CNP-mediated functional responses in failing rat myocardium. British Journal of Pharmacology. ISSN 0007-1188. 170(2), p. 366–379. doi: 10.1111/bph.12282. Full text in Research Archive
• Brudeli, Bjarne; Moltzau, Lise Roman; Nguyen, Hong Cam Thi; Andressen, Kjetil Wessel; Nilsen, Nils Olav & Levy, Finn Olav [Show all 7 contributors for this article] (2013). Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist. European Journal of Medicinal Chemistry. ISSN 0223-5234. 64, p. 629–637. doi: 10.1016/j.ejmech.2013.03.060. Full text in Research Archive
• Brudeli, Bjarne; Andressen, Kjetil Wessel; Moltzau, Lise Roman; Nilsen, Nils Olav; Levy, Finn Olav & Klaveness, Jo (2013). Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 21(22), p. 7134–7145. doi: 10.1016/j.bmc.2013.09.004. Full text in Research Archive
• Brattelid, Trond; Qvigstad, Eirik; Moltzau, Lise Roman; Bekkevold, Silje Veslemøy; Sandnes, Dagny Lise & Birkeland, Jon Arne [Show all 10 contributors for this article] (2012). The Cardiac Ventricular 5-HT4 Receptor Is Functional in Late Foetal Development and Is Reactivated in Heart Failure. PLOS ONE. 7(9). doi: 10.1371/journal.pone.0045489. Full text in Research Archive Show summary

  A positive inotropic responsiveness to serotonin, mediated by 5-HT4 and 5-HT2A receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT4, 5-HT2A and 5-HT2B serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function ex vivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT4 mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT2A and 5-HT2B receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT2A receptor mediated a positive inotropic response. We suggest that the 5-HT4 receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.

• Afzal, Faraz; Aronsen, Jan Magnus; Moltzau, Lise Roman; Sjaastad, Ivar; Levy, Finn Olav & Skomedal, Tor [Show all 8 contributors for this article] (2011). Differential regulation of beta(2)-adrenoceptor-mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non-failing rat cardiac ventricle. British Journal of Pharmacology. ISSN 0007-1188. 162(1), p. 54–71. doi: 10.1111/j.1476-5381.2010.00890.x. Full text in Research Archive
• Afzal, Faraz; Qvigstad, Eirik; Aronsen, Jan Magnus; Moltzau, Lise Roman; Sjaastad, Ivar & Skomedal, Tor [Show all 8 contributors for this article] (2011). Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle. Naunyn-Schmiedeberg's Archives of Pharmacology. ISSN 0028-1298. 384(6), p. 543–553. doi: 10.1007/s00210-011-0670-6. Full text in Research Archive
• Berrade, Luis; Aisa, Bárbara; Ramirez, María; Galiano, Silvia; Guccione, Salvatore & Moltzau, Lise Roman [Show all 13 contributors for this article] (2011). Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action. Journal of Medicinal Chemistry. ISSN 0022-2623. 54(8), p. 3086–3090. doi: 10.1021/jm2000773. Full text in Research Archive
• Qvigstad, Eirik; Moltzau, Lise Roman; Aronsen, Jan Magnus; Nguyen, Hong Cam Thi; Hougen, Karina & Sjaastad, Ivar [Show all 9 contributors for this article] (2010). Natriuretic peptides increase beta(1)-adrenoceptor signalling in failing hearts through phosphodiesterase 3 inhibition. Cardiovascular Research (CVR). ISSN 0008-6363. 85(4), p. 763–772. doi: 10.1093/cvr/cvp364. Full text in Research Archive
• Brudeli, Bjarne; Moltzau, Lise Roman; Andressen, Kjetil Wessel; Krobert, Kurt Allen; Klaveness, Jo & Levy, Finn Olav (2010). Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 18(24), p. 8600–8613. doi: 10.1016/j.bmc.2010.10.011. Full text in Research Archive
• Kloster, Martine Müller; Hafte, Tolesa Tilahun; Moltzau, Lise Roman; Hallan, Elin; Dahle, Maria Krutå & Skålhegg, Bjørn Steen [Show all 10 contributors for this article] (2008). EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase. Cellular Signalling. ISSN 0898-6568. 20(6), p. 1169–1178. doi: 10.1016/j.cellsig.2008.02.007. Full text in Research Archive

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• Marshall, Serena; Aronsen, Jan Magnus; Skogestad, Jonas; Albert, Ingrid; Lothe, Gustav B & Lunde, Per Kristian [Show all 13 contributors for this article] (2015). Dual PDE3A coupling to AKAP18 and SERCA2 Controls SERCA2 Activity in adult cardiomyocytes. Full text in Research Archive
• Meier, Silja; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Skomedal, Tor & Osnes, Jan-Bjørn [Show all 9 contributors for this article] (2015). Enhancement of cAMP-mediated inotropic responses by CNP is regulated differently by PDE2 in normal and failing hearts. BMC Pharmacology and Toxicology. 16, p. A66–A66. doi: 10.1186/2050-6511-16-S1-A66. Full text in Research Archive
• Meier, Silja; Moltzau, Lise Roman; Aronsen, Jan Magnus; Sjaastad, Ivar; Skomedal, Tor & Osnes, Jan-Bjørn [Show all 8 contributors for this article] (2014). Enhancement of B1 - adrenoceptor signaling by CNP through NPR-B and regulation by phosphodiesterases in normal and failing hearts. Full text in Research Archive
• Aronsen, Jan Magnus; Hougen, Karina; Skogestad, Jonas; Lunde, Marianne; Enger, Ulla Helene & Moltzau, Lise Roman [Show all 11 contributors for this article] (2013). PDE3A is part of the SERCA2-AKAP18 macromolecular complex in cardiomyocytes. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Sjaastad, Ivar; Skomedal, Tor & Osnes, Jan-Bjørn [Show all 8 contributors for this article] (2012). NPR-A and NPR-B signal in different functional compartments in failing rat left ventricle. Cardiovascular Research (CVR). ISSN 0008-6363. 93, p. S18–S18. doi: 10.1093/cvr/cvr332. Full text in Research Archive
• Aronsen, Jan Magnus; Aronsen, Jan Magnus; Hougen, Karina; Skogestad, Jonas; Enger, Ulla Helene & Moltzau, Lise Roman [Show all 11 contributors for this article] (2012). PDE3A is part of the SERCA2-AKAP18 macromolecular complex in cardiomyocytes. Full text in Research Archive
• Hougen, Karina; Aronsen, Jan Magnus; Skogestad, Jonas; Enger, Ulla Helene; Moltzau, Lise Roman & Qvigstad, Eirik [Show all 10 contributors for this article] (2012). PDE3A is part of the SERCA2-AKAP18delta macromolecular complex in cardiomyocytes. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Nguyen, Cam; Christensen, Geir Arve & Sjaastad, Ivar [Show all 10 contributors for this article] (2011). The negative inotropic and positive lusitropic responses to CNP are dependent on SERCA2 activity in failing rat ventricle. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Nguyen, Cam; Christensen, Geir Arve & Sjaastad, Ivar [Show all 10 contributors for this article] (2011). The mechanism of CNP-induced negative inotropic and positive lusitropic responses are dependent on SERCA activity in failing rat ventricle. Full text in Research Archive
• Qvigstad, Eirik; Afzal, Faraz; Aronsen, Jan Magnus; Moltzau, Lise Roman; Sjaastad, Ivar & Skomedal, Tor [Show all 8 contributors for this article] (2010). The NO/cyclic GMP signalling pathway differentially affects 5-HT4 - and B1-AR mediated inotropic responses in failing ventricle. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Meier, Silja; Nguyen, Hong Cam Thi; Afzal, Faraz & Sjaastad, Ivar [Show all 10 contributors for this article] (2010). Compartmentation of the cGMP signal causes differential functional responses after CNP and BNP stimulation in failing myocardium. Full text in Research Archive
• Afzal, Faraz; Aronsen, Jon magnus; Moltzau, Lise Roman; Sjaastad, Ivar; Levy, Finn Olav & Skomedal, Tor [Show all 8 contributors for this article] (2009). Differential regulation of b2-adrenoceptor-mediated responses by PDE3 and PDE4 in failing and non-failing rat myocardium. Full text in Research Archive
• Moltzau, Lise Roman; Aronsen, Jan Magnus; Nguyen, Hong Cam Thi; Sjaastad, Ivar; Afzal, Faraz & Skomedal, Tor [Show all 9 contributors for this article] (2008). Phospodiesterases regulating the negative inotropic response of C-type natriuretic peptide in heart failure. Fundamental & Clinical Pharmacology. ISSN 0767-3981. 22, p. 17–17. Full text in Research Archive
• Afzal, Faraz; Andressen, Kjetil Wessel; Mørk, Halvor Kjeang; Aronsen, Jon magnus; Moltzau, Lise Roman & Sjaastad, Ivar [Show all 10 contributors for this article] (2007). 5-HT4-mediated positive inotropic effect is regulated by phosphodiesterase 3 in failing rat heart and human ventricle. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 42(6), p. S152–S152. Full text in Research Archive
• Brattelid, Trond; Bekkevold, Silje Veslemøy; Qvigstad, Eirik; Moltzau, Lise Roman; Sandnes, Dagny Lise & Birkeland, Jon Arne [Show all 8 contributors for this article] (2006). The 5-HT4 receptor - a foetal gene reactivated in heart failure? Journal of Pharmacological Sciences (JPS). ISSN 1347-8613. 101, p. 76–76. Full text in Research Archive
• Brattelid, Trond; Bekkevold, Silje Veslemøy; Qvigstad, Eirik; Moltzau, Lise Roman; Sandnes, Dagny Lise & Birkeland, Jon Arne [Show all 8 contributors for this article] (2006). The 5-HT4 receptor - a foetal gene reactivated in heart failure? Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 40, p. 944–944. Full text in Research Archive

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