# The serotonin receptor 2b (5-HT2B) modulates heart remodeling following myocardial infarction via regulation of Hippo pathway **Authors:** Ryan Potter, Min Zi, Sukhpal Prehar, Tara McNulty, Dowan Kwon, Ellie England, Maram Almutairi, Nicholas Stafford, Ardiansah Bayu Nugroho, Efta Triastuti, Luc Maroteaux, Elizabeth J. Cartwright, Delvac Oceandy PMC · DOI: 10.1016/j.isci.2026.114825 · iScience · 2026-01-27 ## TL;DR This study shows that the serotonin receptor 5-HT2B influences heart recovery after a heart attack by controlling the Hippo pathway, which affects cell growth and survival. ## Contribution The study reveals a novel regulatory role of 5-HT2B in the Hippo/YAP pathway in cardiomyocytes following myocardial infarction. ## Key findings - 5-HT2B enhances Hippo pathway activity and YAP function, promoting cardiomyocyte proliferation and survival. - Overexpression of 5-HT2B in mice worsens heart remodeling after MI, while modRNA-mediated expression is partially protective. - The compound SB204741 modulates the Hippo/YAP pathway and protects the heart from adverse remodeling after MI. ## Abstract Myocardial infarction (MI) is a leading cause of death globally. Following MI, the heart undergoes remodeling leading to heart failure. The Hippo pathway is a major regulator of cell growth and survival in cardiomyocytes. Here, we show that serotonin receptor 2B (5-HT2B) regulates the Hippo pathway in cardiomyocytes and modulates heart remodeling following MI. 5-HT2B expression significantly enhanced the Hippo pathway effector Yes-associated protein (YAP) activity resulting in increased cardiomyocyte proliferation and decreased apoptosis. However, transgenic mice overexpressing 5-HT2B in cardiomyocytes had a lower survival rate post-MI. Conversely, modified mRNA (modRNA)-mediated transient 5-HT2B expression in the heart was sufficient to inhibit post-MI remodeling. Pharmacological screening of serotonergic compounds identified SB204741 as a modulator of the Hippo/YAP pathway in cardiomyocytes. SB204741 has been shown to protect the heart from adverse remodeling post-MI. Our findings identify 5-HT2B as a regulator of the Hippo pathway that can be targeted to improve cardiac phenotype following MI. •Serotonin receptor 2B (5HT2B) regulates the Hippo pathway and activates YAP in cardiomyocytes•5HT2B promotes cardiomyocyte proliferation and survival in vitro•Transgenic overexpression of 5HT2B exacerbates hypertrophic remodeling following MI•modRNA delivery of exogenous 5HT2B was partially protective against MI-induced remodeling Serotonin receptor 2B (5HT2B) regulates the Hippo pathway and activates YAP in cardiomyocytes 5HT2B promotes cardiomyocyte proliferation and survival in vitro Transgenic overexpression of 5HT2B exacerbates hypertrophic remodeling following MI modRNA delivery of exogenous 5HT2B was partially protective against MI-induced remodeling Biochemical mechanism; Human metabolism; Molecular network ## Linked entities - **Genes:** HTR2B (5-hydroxytryptamine receptor 2B) [NCBI Gene 3357], YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] - **Chemicals:** SB204741 (PubChem CID 3277600) - **Diseases:** myocardial infarction (MONDO:0005068), heart failure (MONDO:0005252) ## Full-text entities - **Genes:** Rhoa (ras homolog family member A) [NCBI Gene 11848] {aka Arha, Arha1, Arha2}, Tnni3 (troponin I, cardiac 3) [NCBI Gene 21954] {aka Tn1, cTnI}, WWTR1 (WW domain containing transcription regulator 1) [NCBI Gene 25937] {aka TAZ}, Htr1a (5-hydroxytryptamine (serotonin) receptor 1A) [NCBI Gene 15550] {aka Gpcr18}, Sav1 (salvador family WW domain containing 1) [NCBI Gene 64010] {aka 1700040G09Rik, Salv, Sav, WW45, Wwp3, Wwp4}, Yap1 (yes-associated protein 1) [NCBI Gene 22601] {aka Yap, Yap65, Yki, Yorkie}, Htr2b (5-hydroxytryptamine (serotonin) receptor 2B) [NCBI Gene 15559] {aka 5-HT-2B, 5-HT-2F, 5-HT2B}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, SAV1 (salvador family WW domain containing protein 1) [NCBI Gene 60485] {aka SAV, WW45, WWP4}, HTR2A (5-hydroxytryptamine receptor 2A) [NCBI Gene 3356] {aka 5-HT2A, HTR2}, Lats1 (large tumor suppressor) [NCBI Gene 16798], PRRT2 (proline rich transmembrane protein 2) [NCBI Gene 112476] {aka BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA}, Mapk1 (mitogen-activated protein kinase 1) [NCBI Gene 26413] {aka 9030612K14Rik, ERK, Erk2, MAPK2, PRKM2, Prkm1}, ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, Adgre1 (adhesion G protein-coupled receptor E1) [NCBI Gene 13733] {aka DD7A5-7, EGF-TM7, Emr1, F4/80, Gpf480, Ly71}, Htr2b (5-hydroxytryptamine receptor 2B) [NCBI Gene 29581] {aka 5-HT-2B, 5-HT-2F, 5-HT2B}, Adra1d (adrenergic receptor, alpha 1d) [NCBI Gene 11550] {aka Adra-1, Adra1, Adra1a, Gpcr8, Spr8, [a]1d}, GLB1 (galactosidase beta 1) [NCBI Gene 2720] {aka EBP, ELNR1, MPS4B}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, Map3k10 (mitogen-activated protein kinase kinase kinase 10) [NCBI Gene 269881] {aka MST, Mlk2}, Yap1 (Yes1 associated transcriptional regulator) [NCBI Gene 363014] {aka YAP65, Yap}, HTR7 (5-hydroxytryptamine receptor 7) [NCBI Gene 3363] {aka 5-HT7}, Sgms1 (sphingomyelin synthase 1) [NCBI Gene 353229] {aka Mob, Tmem23, mob-1}, YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] {aka COB1, YAP, YAP-1, YAP2, YAP65, YKI}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, HTR2B (5-hydroxytryptamine receptor 2B) [NCBI Gene 3357] {aka 5-HT(2B), 5-HT-2B, 5-HT2B}, Myh6 (myosin, heavy polypeptide 6, cardiac muscle, alpha) [NCBI Gene 17888] {aka A830009F23Rik, Myhc-a, Myhca, alpha-MHC, alphaMHC}, H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, Ppp1r12a (protein phosphatase 1, regulatory subunit 12A) [NCBI Gene 17931] {aka 1200015F06Rik, 5730577I22Rik, D10Ertd625e, Mypt1}, ACTN1 (actinin alpha 1) [NCBI Gene 87] {aka BDPLT15}, HSPG2 (heparan sulfate proteoglycan 2) [NCBI Gene 3339] {aka HSPG, PLC, PRCAN, SJA, SJS, SJS1}, FYN (FYN proto-oncogene, Src family tyrosine kinase) [NCBI Gene 2534] {aka SLK, SYN, p59-FYN}, LGALS4 (galectin 4) [NCBI Gene 3960] {aka GAL4, L36LBP}, HTR1A (5-hydroxytryptamine receptor 1A) [NCBI Gene 3350] {aka 5-HT-1A, 5-HT1A, 5HT1a, ADRB2RL1, ADRBRL1, G-21}, HTR4 (5-hydroxytryptamine receptor 4) [NCBI Gene 3360] {aka 5-HT4, 5-HT4R}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 24383] {aka BARS-38, Gapd}, GPR166P (G protein-coupled receptor 166, pseudogene) [NCBI Gene 442206] {aka GPCR, PGR9}, Lats1 (large tumor suppressor kinase 1) [NCBI Gene 308265] {aka RGD1564085}, Sav1 (salvador family WW domain containing protein 1) [NCBI Gene 299116], TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 6901] {aka BTHS, CMD3A, EFE, EFE2, G4.5, LVNCX}, DNTT (DNA nucleotidylexotransferase) [NCBI Gene 1791] {aka TDT}, ROCK1 (Rho associated coiled-coil containing protein kinase 1) [NCBI Gene 6093] {aka P160ROCK, ROCK-I}, Bax (BCL2-associated X protein) [NCBI Gene 12028], Casp9 (caspase 9) [NCBI Gene 12371] {aka APAF-3, CASP-9, Caspase-9, ICE-LAP6, Mch6}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, Dntt (deoxynucleotidyltransferase, terminal) [NCBI Gene 21673] {aka Tdt}, Slc25a4 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 4) [NCBI Gene 11739] {aka Ant1, mANC1}, MOB1A (MOB kinase activator 1A) [NCBI Gene 55233] {aka C2orf6, MABKL1B, MATS1, MOB1, MOBK1B, MOBKL1B}, SRC (SRC proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 6714] {aka ASV, SRC1, THC6, c-SRC, p60-Src}, LATS1 (large tumor suppressor kinase 1) [NCBI Gene 9113] {aka WARTS, wts} - **Diseases:** tissue injury (MESH:D017695), necrosis (MESH:D009336), dislocation (MESH:D004204), cardiac damage (MESH:D006331), cardiac adverse remodeling (MESH:D020257), cardiac dilatation and hypertrophy (MESH:D006332), HF (MESH:D006333), Infarct (MESH:D007238), cytotoxicity (MESH:D064420), I/R hearts (MESH:C580424), hypertrophy (MESH:D006984), ischemic injury (MESH:D017202), dilatation (MESH:D002311), infection (MESH:D007239), coagulation (MESH:D001778), Heart attack (MESH:D009203), colon cancer (MESH:D015179), ventricular hypertrophy (MESH:D024741), death (MESH:D003643), IR (MESH:D015427), mass (MESH:C536030), ischaemia (MESH:D007511), sudden cardiac death (MESH:D016757), cardiac rupture (MESH:D006341), cardiomyopathy (MESH:D009202), arrhythmia (MESH:D001145), neonatal lethality (MESH:C537510), tumor (MESH:D009369), rupture (MESH:D012421), ischemic (MESH:D002545), cardiomyocyte loss (MESH:D016388), fibrosis (MESH:D005355), cardiac inflammation (MESH:D007249) - **Chemicals:** Poly(A) (MESH:D011061), alkyne (MESH:D000480), phosphomolybdic acid (MESH:C003125), 4',6-diamidino-2-phenylindole (MESH:C007293), DMSO (MESH:D004121), Videne (MESH:D011206), glucose (MESH:D005947), 5-HT (MESH:D012701), pepstatin A (MESH:C031375), DAB (MESH:C000469), Bouin's solution (MESH:C026239), DAG (MESH:D004075), Tween 20 (MESH:D011136), KCl (MESH:D011189), buprenorphine (MESH:D002047), Agarose (MESH:D012685), PFA (MESH:C003043), ammonium acetate (MESH:C018824), dabuzalgron (MESH:C481520), BCA (MESH:C047117), CO2 (MESH:D002245), Aniline blue (MESH:C017006), Alexa Fluor 488 (MESH:C000711379), fatty acid (MESH:D005227), SB204741 (MESH:C092756), L-ascorbic acid 2-phosphate (MESH:C011669), thymidine (MESH:D013936), MgSO4 (MESH:D008278), prilocaine (MESH:D011318), Picrosirius Red (MESH:C009798), dUTP (MESH:C027078), Lipofectamine (MESH:C086724), amphotericin B (MESH:D000666), phenylmethylsulfonyl fluoride (MESH:D010664), fluorescein (MESH:D019793), HEPES (MESH:D006531), Haematoxylin (MESH:D006416), AlexaFluor 647 (MESH:C569686), penicillin (MESH:D010406), copper sulphate (MESH:D019327), doxorubicin (MESH:D004317), sodium citrate (MESH:D000077559), lidocaine (MESH:D008012), Ipsapirone (MESH:C043077), IMS (-), H2O2 (MESH:D006861), B- (MESH:D001895), glycine (MESH:D005998), kanamycin (MESH:D007612), ethanol (MESH:D000431), hydrochloric acid (MESH:D006851), TAE buffer (MESH:C115179), 5-ethynyl-2'-deoxyuridine (MESH:C031086), Cu+ (MESH:D003300), SDS (MESH:D012967), isopropanol (MESH:D019840), acetic acid (MESH:D019342), essential amino acids (MESH:D000601), Laemmli buffer (MESH:C088816), CHIR99021 (MESH:C473711) - **Species:** Drosophila melanogaster (fruit fly, species) [taxon 7227], Homo sapiens (human, species) [taxon 9606], Adenoviridae (family) [taxon 10508], Rattus norvegicus (brown rat, species) [taxon 10116], Mycoplasma (genus) [taxon 2093], Mus musculus (house mouse, species) [taxon 10090], Escherichia coli (E. coli, species) [taxon 562] - **Mutations:** F566S - **Cell lines:** /6J — Homo sapiens (Human), Cutaneous melanoma, Cancer cell line (CVCL_W797), NIH/3T3 — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0594), HEK293 — Homo sapiens (Human), Transformed cell line (CVCL_0045), A18944 — Homo sapiens (Human), Transformed cell line (CVCL_P029), NRCMs — Coturnix japonica (Japanese quail), Transformed cell line (CVCL_J504), C57BL/6J — Mus musculus (Mouse), Transformed cell line (CVCL_C0MW), H9C2 — Rattus norvegicus (Rat), Spontaneously immortalized cell line (CVCL_0286), NIH/3T3 fibroblasts — Mus musculus (Mouse), Transformed cell line (CVCL_L992), S2 — Drosophila melanogaster (Fruit fly), Spontaneously immortalized cell line (CVCL_Z232), B8175 — Ceratotherium simum cottoni (Northern white rhinoceros), Induced pluripotent stem cell (CVCL_TZ75) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12915196/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12915196/full.md ## References 49 references — full list in the complete paper: https://tomesphere.com/paper/PMC12915196/full.md --- Source: https://tomesphere.com/paper/PMC12915196