Molecular Cardiology

In our laboratory, we investigate the biological basis of sex differences in cardiovascular health and disease. We examine the molecular mechanisms and dynamic processes underlying exercise-induced cardioprotection, with particular attention to sex-specific pathways and responses. 

Our overarching objective is to elucidate how regular physical activity triggers protective mechanisms in the cardiovascular system – mechanisms that differ between men and women. By establishing these molecular underpinnings, we aim to unlock strategies for both preventing and treating cardiovascular diseases, including heart failure and chemotherapy-induced cardiotoxicity. 

• Kumari M, Evangelakos I, Deshpande A, De Jong KA, Schmiedel N, Palacio-Escat N, Chaves-Filho AB, Frias-Soler RC, Klinke G, Roh HC, Lange L, Berlin M, Fuh MM, Buss JJ, Tian T, Lerchenmüller C, Freichel M, Schulze A, Nikolaev VO, Eschenhagen T, Rosen ED, Scheja L, Rangrez AY, Heeren J, Frey N. Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure. Nat Commun. 2026 Feb 27;17(1):2051. doi: 10.1038/s41467-026-69792-4. PMID: 41760613; PMCID: PMC12948977.

• Kang J, Chouvardas P, Maalouf A, Hanhart D, Cerro LF, Cheng W, Compérat E, Ovchinnikova K, Etter R, Medová M, Schneeberger U, Roth B, Thalmann GN, Karkampouna S, Kruithof-de Julio M. Multi-layer stratified oncology platform utilizing transcriptomics, prostate cancer organoids, and modeling of drug response.J Exp Clin Cancer Res. 2025 Oct 16;44(1):290. doi: 10.1186/s13046-025-03540-2. PMID: 41094672; PMCID: PMC12529805. 

• Hastings MH, Zhou Q, Wu C, Shabani P, Huang S, Yu X, Singh AP, Guseh JS, Li H, Lerchenmüller C, Rosenzweig A.Cardiac ageing: from hallmarks to therapeutic opportunities.
  Cardiovasc Res. 2025 Aug 28;121(10):1474-1488. doi: 10.1093/cvr/cvae124. PMID: 38918884; PMCID: PMC12391674. 

• Heming JN, Margraf A, Najder K, Germena G, Richter M, Cappenberg A, Henke K, Bardel B, Schemmelmann L, Oguama M, Lindental P, Amini W, Sobocik J, Schett G, Krönke G, Block H, Rossaint J, Soehnlein O, Zarbock A. CD45 and CD148 Are Critically Involved in Neutrophil Recruitment and Function During Inflammatory Arthritis in Mice.Cells. 2025 Jul 29;14(15):1169. doi: 10.3390/cells14151169. PMID: 40801601; PMCID: PMC12346378. 

• Khetarpal SA, Li H, Lerchenmüller C, Rhee J, Rosenzweig A. Molecular Mediators of the Cardiac Benefits of Exercise.
  Circ Res. 2025 Jul 7;137(2):163-183. doi: 10.1161/CIRCRESAHA.125.325762. Epub 2025 Jul 3. PMID: 40608861. 

• Manickam N, Sultan I, Panthel J, Kujundzic H, Fischer A, Schmitz K, Ruz Jurado M, Morales DR, John D, Glaser SF, Stilz KA, Malacarne PF, Brandes RP, Braun T, Lerchenmüller C, Betge F, Abplanalp WT, Alitalo K, Dimmeler S, Wagner JUG. Beneficial effects of vascular endothelial growth factor B gene transfer in the aged heart.
  Cardiovasc Res. 2025 Mar 21:cvaf046. doi: 10.1093/cvr/cvaf046. Epub ahead of print. PMID: 40116846. 

• Lerchenmüller C, Hastings MH, Rabolli CP, Betge F, Roshan M, Liu LX, Liu X, Heß C, Roh JD, Platt C, Bezzerides V, Busch M, Katus HA, Frey N, Most P, Rosenzweig A. CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice.
  Mol Ther. 2024 Oct 2;32(10):3683-3694. doi: 10.1016/j.ymthe.2024.07.018. Epub 2024 Jul 26. PMID: 39066479; PMCID: PMC11489533. 

• Wu J, Bley M, Steans RS, Meadows AM, Huffstutler RD, Tian R, Griffin JL, Sack MN. Nicotinamide Riboside Augments Human Macrophage Migration via SIRT3-Mediated Prostaglandin E2 Signaling.Cells. 2024 Mar 5;13(5):455. doi: 10.3390/cells13050455. PMID: 38474420; PMCID: PMC10931126. 

• Hastings MH, Castro C, Freeman R, Abdul Kadir A, Lerchenmüller C, Li H, Rhee J, Roh JD, Roh K, Singh AP, Wu C, Xia P, Zhou Q, Xiao J, Rosenzweig A. Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise.
  JACC Basic Transl Sci. 2023 Oct 18;9(4):535-552. doi: 10.1016/j.jacbts.2023.07.011. PMID: 38680954; PMCID: PMC11055208. 

• Roh JD, Castro C, Yu A, Rana S, Shahul S, Gray KJ, Honigberg MC, Ricke-Hoch M, Iwamoto Y, Yeri A, Kitchen R, Guerra JB, Hobson R, Chaudhari V, Chang B, Sarma A, Lerchenmüller C, Al Sayed ZR, Diaz Verdugo C, Xia P, Skarbianskis N, Zeisel A, Bauersachs J, Kirkland JL, Karumanchi SA, Gorcsan J 3rd, Sugahara M, Damp J, Hanley-Yanez K, Ellinor PT, Arany Z, McNamara DM; IPAC Investigators; Hilfiker-Kleiner D, Rosenzweig A. Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.Sci Transl Med. 2024 Apr 17;16(743):eadi0077. doi: 10.1126/scitranslmed.adi0077. Epub 2024 Apr 17. PMID: 38630848; PMCID: PMC11331492. 

• Liu X, Li H, Hastings MH, Xiao C, Damilano F, Platt C, Lerchenmüller C, Zhu H, Wei XP, Yeri A, Most P, Rosenzweig A.
  miR-222 inhibits pathological cardiac hypertrophy and heart failure.
  Cardiovasc Res. 2024 Mar 14;120(3):262-272. doi: 10.1093/cvr/cvad184. PMID: 38084908; PMCID: PMC10939454. 

• Mastini C, Campisi M, Patrucco E, Mura G, Ferreira A, Costa C, Ambrogio C, Germena G, Martinengo C, Peola S, Mota I, Vissio E, Molinaro L, Arigoni M, Olivero M, Calogero R, Prokoph N, Tabbò F, Shoji B, Brugieres L, Geoerger B, Turner SD, Cuesta-Mateos C, D'Aliberti D, Mologni L, Piazza R, Gambacorti-Passerini C, Inghirami GG, Chiono V, Kamm RD, Hirsch E, Koch R, Weinstock DM, Aster JC, Voena C, Chiarle R. Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma.Sci Transl Med. 2023 Jun 28;15(702):eabo3826. doi: 10.1126/scitranslmed.abo3826. Epub 2023 Jun 28. PMID: 37379367; PMCID: PMC10804420. 

• Samak M, Kues A, Kaltenborn D, Klösener L, Mietsch M, Germena G, Hinkel R. Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes.Int J Mol Sci. 2023 Jan 27;24(3):2482. doi: 10.3390/ijms24032482.  

• Schoger E, Bleckwedel F, Germena G, Rocha C, Tucholla P, Sobitov I, Möbius W, Sitte M, Lenz C, Samak M, Hinkel R, Varga ZV, Giricz Z, Salinas G, Gross JC, Zelarayán LC. Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling.Commun Biol. 2023 Jan 21;6(1):79. doi: 10.1038/s42003-022-04402-9. Erratum in: Commun Biol. 2024 May 23;7(1):624. doi: 10.1038/s42003-024-06319-x. PMID: 36681760; PMCID: PMC9867722. 

• Lerchenmüller C, Vujic A, Mittag S, Wang A, Rabolli CP, Heß C, Betge F, Rangrez AY, Chaklader M, Guillermier C, Gyngard F, Roh JD, Li H, Steinhauser ML, Frey N, Rothermel B, Dieterich C, Rosenzweig A, Lee RT. Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise.
  Circulation. 2022 Aug 2;146(5):412-426. doi: 10.1161/CIRCULATIONAHA.121.057276. Epub 2022 Jul 6. PMID: 35862076; PMCID: PMC9357140. 

• Germena G, Zelarayán LC, Hinkel R. Cellular Chitchatting: Exploring the Role of Exosomes as Cardiovascular Risk Factors.
  Front Cell Dev Biol. 2022 Mar 31;10:860005. doi: 10.3389/fcell.2022.860005. PMID: 35433670; PMCID: PMC9008366. 

• Wu J, Singh K, Lin A, Meadows AM, Wu K, Shing V, Bley M, Hassanzadeh S, Huffstutler RD, Schmidt MS, Blanco LP, Tian R, Brenner C, Pirooznia M, Kaplan MJ, Sack MN.
  Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.J Clin Invest. 2022 Mar 1;132(5):e139828. doi: 10.1172/JCI139828. PMID: 35025762; PMCID: PMC8884917. 

• Kang J, La Manna F, Bonollo F, Sampson N, Alberts IL, Mingels C, Afshar-Oromieh A, Thalmann GN, Karkampouna S. Tumor microenvironment mechanisms and bone metastatic disease progression of prostate cancer.Cancer Lett. 2022 Apr 1;530:156-169. doi: 10.1016/j.canlet.2022.01.015. Epub 2022 Jan 17. PMID: 35051532. 

• Samak M, Kaltenborn D, Kues A, Le Noble F, Hinkel R, Germena G. Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes. Biomedicines. 2021 Dec 28;10(1):58. doi: 10.3390/biomedicines10010058. PMID: 35052738; PMCID: PMC8773250. 

• Germena G, Hinkel R.
  iPSCs and Exosomes: Partners in Crime Fighting Cardiovascular Diseases.
  J Pers Med. 2021 Jun 9;11(6):529. doi: 10.3390/jpm11060529. PMID: 34207562; PMCID: PMC8230331. 

• Germena G*, Margraf A*, Drexler HCA, Rossaint J, Ludwig N, Prystaj B, Mersmann S, Thomas K, Block H, Gottschlich W, Liu C, Krenn PW, Haller H, Heitplatz B, Meyer Zu Brickwedde M, Moser M, Vestweber D, Zarbock A. The integrin-linked kinase is required for chemokine-triggered high-affinity conformation of the neutrophil β2-integrin LFA-1.Blood. 2020 Nov 5;136(19):2200-2205. doi: 10.1182/blood.2020004948. PMID: 32730588. *Equal contributors 

• Margraf A, Cappenberg A, Vadillo E, Ludwig N, Thomas K, Körner K, Zondler L, Rossaint J, Germena G, Hirsch E, Zarbock A. ArhGAP15, a RacGAP, Acts as a Temporal Signaling Regulator of Mac-1 Affinity in Sterile Inflammation. 
  J Immunol. 2020 Sep 1;205(5):1365-1375. doi: 10.4049/jimmunol.2000047. Epub 2020 Jul 27. PMID: 32839212. 

• Roh JD, Houstis N, Yu A, Chang B, Yeri A, Li H, Hobson R, Lerchenmüller C, Vujic A, Chaudhari V, Damilano F, Platt C, Zlotoff D, Lee RT, Shah R, Jerosch-Herold M, Rosenzweig A. Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.Aging Cell. 2020 Jun;19(6):e13159. doi: 10.1111/acel.13159. Epub 2020 May 22. PMID: 32441410; PMCID: PMC7294786. 

• Lerchenmüller C, Rabolli CP, Yeri A, Kitchen R, Salvador AM, Liu LX, Ziegler O, Danielson K, Platt C, Shah R, Damilano F, Kundu P, Riechert E, Katus HA, Saffitz JE, Keshishian H, Carr SA, Bezzerides VJ, Das S, Rosenzweig A. CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress. 
  Circ Res. 2020 Aug 14;127(5):631-646. doi: 10.1161/CIRCRESAHA.119.315881. Epub 2020 May 18. PMID: 32418505; PMCID: PMC7725361. 

• Kang J, Sun Y, Deng Y, Liu Q, Li D, Liu Y, Guan X, Tao Z, Wang X. Autophagy-endoplasmic reticulum stress inhibition mechanism of superoxide dismutase in the formation of calcium oxalate kidney stones.Biomed Pharmacother. 2020 Jan;121:109649. doi: 10.1016/j.biopha.2019.109649. Epub 2019 Nov 13. PMID: 31733571. 

• Spinner GR, Stoeck CT, Mathez L, von Deuster C, Federau C, Kozerke S. On probing intravoxel incoherent motion in the heart-spin-echo versus stimulated-echo DWI.
  Magn Reson Med. 2019 Sep;82(3):1150-1163. doi: 10.1002/mrm.27777. Epub 2019 Apr 26. PMID: 31025435. 

• Vujic A, Lerchenmüller C, Wu TD, Guillermier C, Rabolli CP, Gonzalez E, Senyo SE, Liu X, Guerquin-Kern JL, Steinhauser ML, Lee RT, Rosenzweig A. Exercise induces new cardiomyocyte generation in the adult mammalian heart.
  Nat Commun. 2018 Apr 25;9(1):1659. doi: 10.1038/s41467-018-04083-1. PMID: 29695718; PMCID: PMC5916892. 

• Germena G*, Campa CC*, Ciraolo E, Copperi F, Sapienza A, Franco I, Ghigo A, Camporeale A, Di Savino A, Martini M, Perino A, Megens RT, Kurz AR, Scheiermann C, Sperandio M, Gamba A, Hirsch E.
  Rac signal adaptation controls neutrophil mobilization from the bone marrow.
  Sci Signal. 2016 Dec 20;9(459):ra124. doi: 10.1126/scisignal.aah5882. PMID: 27999173. *Equal contributors. 

• Zamboni V, Armentano M, Sarò G, Ciraolo E, Ghigo A, Germena G, Umbach A, Valnegri P, Passafaro M, Carabelli V, Gavello D, Bianchi V, D'Adamo P, de Curtis I, El-Assawi N, Mauro A, Priano L, Ferri N, Hirsch E, Merlo GR. Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons. and causes cognitive deficitsSci Rep. 2016 Oct 7;6:34877. doi: 10.1038/srep34877. PMID: 27713499; PMCID: PMC5054378. 

• Lerchenmüller C, Heißenberg J, Damilano F, Bezzeridis VJ, Krämer I, Bochaton-Piallat ML, Hirschberg K, Busch M, Katus HA, Peppel K, Rosenzweig A, Busch H, Boerries M, Most P. S100A6 Regulates Endothelial Cell Cycle Progression by Attenuating Antiproliferative Signal Transducers and Activators of Transcription 1 Signaling.Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1854-67. doi: 10.1161/ATVBAHA.115.306415. Epub 2016 Jul 7. PMID: 27386938; PMCID: PMC5001879. 

• Bezzerides VJ, Platt C, Lerchenmüller C, Paruchuri K, Oh NL, Xiao C, Cao Y, Mann N, Spiegelman BM, Rosenzweig A. CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury. 
  JCI Insight. 2016 Jun 16;1(9):e85904. doi: 10.1172/jci.insight.85904. PMID: 27430023; PMCID: PMC4945110. 

• Block H, Stadtmann A, Riad D, Rossaint J, Sohlbach C, Germena G, Wu D, Simon SI, Ley K, Zarbock A. Gnb isoforms control a signaling pathway comprising Rac1, Plcβ2, and Plcβ3 leading to LFA-1 activation and neutrophil arrest in vivo.Blood. 2016 Jan 21;127(3):314-24. doi: 10.1182/blood-2015-06-651034. Epub 2015 Oct 14. PMID: 26468229; PMCID: PMC4722285. 

• Germena G, Volmering S, Sohlbach C, Zarbock A. Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation.J Immunol. 2015 Jan 15;194(2):728-38. doi: 10.4049/jimmunol.1401646. Epub 2014 Dec 10. PMID: 25505282. 

• Campa CC, Ciraolo E, Ghigo A, Germena G, Hirsch E. Crossroads of PI3K and Rac pathways.
  Small GTPases. 2015;6(2):71-80. doi: 10.4161/21541248.2014.989789. Epub 2015 May 5. PMID: 25942647; PMCID: PMC4601376. 

• Lerchenmüller C, Rosenzweig A.
  Mechanisms of exercise-induced cardiac growth.
  Drug Discov Today. 2014 Jul;19(7):1003-9. doi: 10.1016/j.drudis.2014.03.010. Epub 2014 Mar 15. PMID: 24637046. 

• Franco I, Gulluni F, Campa CC, Costa C, Margaria JP, Ciraolo E, Martini M, Monteyne D, De Luca E, Germena G, Posor Y, Maffucci T, Marengo S, Haucke V, Falasca M, Perez-Morga D, Boletta A, Merlo GR, Hirsch E. PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function.Dev Cell. 2014 Mar 31;28(6):647-58. doi: 10.1016/j.devcel.2014.01.022. PMID: 24697898; PMCID: PMC4042153. 

• Sen A, Ren S, Lerchenmüller C, Sun J, Weiss N, Most P, Peppel K. MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.
  PLoS One. 2013 Nov 11;8(11):e78684. doi: 10.1371/journal.pone.0078684. PMID: 24244340; PMCID: PMC3823839. 

• Stadtmann A, Germena G, Block H, Boras M, Rossaint J, Sundd P, Lefort C, Fisher CI, Buscher K, Gelschefarth B, Urzainqui A, Gerke V, Ley K, Zarbock A.The PSGL-1-L-selectin signaling complex regulates neutrophil adhesion under flow.
  J Exp Med. 2013 Oct 21;210(11):2171-80. doi: 10.1084/jem.20130664. Epub 2013 Oct 14. PMID: 24127491; PMCID: PMC3804951. 

• Germena G, Hirsch E. PI3Ks and small GTPases in neutrophil migration: two sides of the same coin.
  Mol Immunol. 2013 Aug;55(1):83-6. doi: 10.1016/j.molimm.2012.10.004. Epub 2012 Nov 5. PMID: 23137593. 

• Fumagalli L, Campa CC, Germena G, Lowell CA, Hirsch E, Berton G. Class I phosphoinositide-3-kinases and SRC kinases play a nonredundant role in regulation of adhesion-independent and -dependent neutrophil reactive oxygen species generation.J Immunol. 2013 Apr 1;190(7):3648-60. doi: 10.4049/jimmunol.1201951. Epub 2013 Feb 27. PMID: 23447687; PMCID: PMC4280093. 

• Most P, Lerchenmüller C, Rengo G, Mahlmann A, Ritterhoff J, Rohde D, Goodman C, Busch CJ, Laube F, Heissenberg J, Pleger ST, Weiss N, Katus HA, Koch WJ, Peppel K. S100A1 deficiency impairs postischemic angiogenesis via compromised proangiogenic endothelial cell function and nitric oxide synthase regulation.Circ Res. 2013 Jan 4;112(1):66-78. doi: 10.1161/CIRCRESAHA.112.275156. Epub 2012 Oct 9. PMID: 23048072; PMCID: PMC3760372. 

• Braccini L, Ciraolo E, Martini M, Pirali T, Germena G, Rolfo K, Hirsch E. PI3K keeps the balance between metabolism and cancer.
  Adv Biol Regul. 2012 Sep;52(3):389-405. doi: 10.1016/j.jbior.2012.04.002. Epub 2012 Apr 24. PMID: 22884032. 

• Gai M, Camera P, Dema A, Bianchi F, Berto G, Scarpa E, Germena G, Di Cunto F. Citron kinase controls abscission through RhoA and anillin.
  Mol Biol Cell. 2011 Oct;22(20):3768-78. doi: 10.1091/mbc.E10-12-0952. Epub 2011 Aug 17. PMID: 21849473; PMCID: PMC3192857. 

• Brinks H, Rohde D, Voelkers M, Qiu G, Pleger ST, Herzog N, Rabinowitz J, Ruhparwar A, Silvestry S, Lerchenmüller C, Mather PJ, Eckhart AD, Katus HA, Carrel T, Koch WJ, Most P. S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes.
  J Am Coll Cardiol. 2011 Aug 23;58(9):966-73. doi: 10.1016/j.jacc.2011.03.054. PMID: 21851887; PMCID: PMC3919460. 

• Germena G*, Costa C*, Martin-Conte EL, Molineris I, Bosco E, Marengo S, Azzolino O, Altruda F, Ranieri VM, Hirsch E. The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions.
  Blood. 2011 Jul 28;118(4):1099-108. doi: 10.1182/blood-2010-12-324756. Epub 2011 May 6. PMID: 21551229. *Equal contributors. 

• Costa C, Germena G, Hirsch E. Dissection of the interplay between class I PI3Ks and Rac signaling in phagocytic functions. ScientificWorldJournal. 2010 Sep 14;10:1826-39. doi: 10.1100/tsw.2010.178. PMID: 20852826; PMCID: PMC5763975. 

• Kraus C, Rohde D, Weidenhammer C, Qiu G, Pleger ST, Voelkers M, Boerries M, Remppis A, Katus HA, Most P. S100A1 in cardiovascular health and disease: closing the gap between basic science and clinical therapy.J Mol Cell Cardiol. 2009 Oct;47(4):445-55. doi: 10.1016/j.yjmcc.2009.06.003. Epub 2009 Jun 16. PMID: 19538970; PMCID: PMC2739260.