α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor.
| Title: | α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor. |
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| Authors: | Suominen A; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Drug Research Doctoral Programme (DRDP), University of Turku, Turku, Finland.; Saldo Rubio G; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Ruohonen S; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Szabó Z; Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.; Pohjolainen L; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.; Ghimire B; Institute for Molecular Medicine Finland (FIMM), HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Faculty of Medicine, University of Turku, Turku, Finland.; Ruohonen ST; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Saukkonen K; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Ijas J; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Skarp S; Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.; Kaikkonen L; Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.; Cai M; Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.; Wardlaw SL; Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.; Ruskoaho H; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.; Talman V; Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.; Savontaus E; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.; Kerkelä R; Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.; Biocenter Oulu, University of Oulu, Oulu, Finland.; Rinne P; Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland. pperin@utu.fi.; Turku Center for Disease Modeling, University of Turku, Turku, Finland. pperin@utu.fi. |
| Source: | EMBO reports [EMBO Rep] 2024 Apr; Vol. 25 (4), pp. 1987-2014. Date of Electronic Publication: 2024 Mar 07. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 100963049 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-3178 (Electronic) Linking ISSN: 1469221X NLM ISO Abbreviation: EMBO Rep Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2024- : [London] : Nature Publishing Group; Original Publication: Oxford, UK : Published for EMBO by Oxford University Press, 2000- |
| MeSH Terms: | alpha-MSH*/pharmacology ; Ventricular Remodeling*; Cardiomegaly/genetics ; Mice ; Animals ; Receptors, Corticotropin ; Receptors, Melanocortin ; Fibrosis |
| Abstract: | α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that MC5-R in cardiomyocytes mediates the anti-hypertrophic signaling of α-MSH. Silencing of MC5-R in cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. In conclusion, α-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogs of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.; (© 2024. The Author(s).) |
| References: | Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H397-402. (PMID: 23709599); Curr Res Physiol. 2019 Dec;1:1-10. (PMID: 32699840); Mol Metab. 2016 Aug 05;5(10):807-822. (PMID: 27688995); Circ Res. 2001 Jul 6;89(1):20-5. (PMID: 11440973); J Mol Cell Cardiol. 2022 Apr;165:130-140. (PMID: 34973276); J Clin Invest. 2013 Jan;123(1):37-45. (PMID: 23281408); J Am Chem Soc. 2010 Jun 16;132(23):8115-28. (PMID: 20496895); Semin Immunol. 2022 Jan;59:101603. (PMID: 35341670); Front Immunol. 2021 Nov 19;12:774013. (PMID: 34868038); Circulation. 2017 Jul 4;136(1):83-97. (PMID: 28450348); Oncotarget. 2017 Jul 18;8(29):47642-47654. (PMID: 28514752); Cardiovasc Res. 2002 Feb 1;53(2):304-12. (PMID: 11827680); Eur J Pharmacol. 2011 Jun 11;660(1):125-30. (PMID: 21208602); Nature. 1979 Mar 29;278(5703):423-7. (PMID: 221818); J Am Coll Cardiol. 2014 Apr 1;63(12):1123-1133. (PMID: 24491689); Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H253-60. (PMID: 21536850); J Med Chem. 1989 Dec;32(12):2555-61. (PMID: 2555512); Cardiovasc Res. 2013 Feb 1;97(2):360-8. (PMID: 23131503); J Mol Cell Cardiol. 2003 Dec;35(12):1385-94. (PMID: 14654364); J Mol Cell Cardiol. 2010 Aug;49(2):294-303. (PMID: 20430035); Neurochem Res. 1995 Jan;20(1):107-13. (PMID: 7739752); J Med Chem. 2000 Dec 28;43(26):4998-5002. (PMID: 11150170); Mol Pharmacol. 2004 Jul;66(1):1-7. (PMID: 15213289); Science. 1992 Aug 28;257(5074):1248-51. (PMID: 1325670); Cardiovasc Res. 1999 Jul;43(1):107-16. (PMID: 10536695); Mol Cell Biol. 1998 Jun;18(6):3518-26. (PMID: 9584192); J Mol Cell Cardiol. 2000 Oct;32(10):1805-19. (PMID: 11013125); EMBO J. 2003 Oct 1;22(19):5079-89. (PMID: 14517246); Cell Mol Life Sci. 2020 Oct;77(19):3831-3840. (PMID: 32248247); Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3866-71. (PMID: 11891332); Front Pharmacol. 2021 Jan 20;11:553852. (PMID: 33584253); J Med Chem. 2008 May 8;51(9):2701-7. (PMID: 18412316); Circulation. 2020 May 26;141(21):1704-1719. (PMID: 32098504); Endocr Rev. 1988 Feb;9(1):159-79. (PMID: 3286233); Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119); Circ Res. 1998 Oct 5;83(7):752-60. (PMID: 9758646); Arch Toxicol. 2018 Sep;92(9):2897-2911. (PMID: 29987409); J Mol Endocrinol. 2016 May;56(4):T77-97. (PMID: 26880796); N Engl J Med. 2003 May 15;348(20):2007-18. (PMID: 12748317); Biochem Biophys Res Commun. 2002 Apr 12;292(4):1075-80. (PMID: 11944925); J Med Chem. 2002 Oct 10;45(21):4589-93. (PMID: 12361385); Nat Methods. 2014 Aug;11(8):855-60. (PMID: 24930130); Hypertension. 2014 Jun;63(6):1235-40. (PMID: 24688123); J Mol Endocrinol. 1994 Apr;12(2):203-13. (PMID: 8060485); J Mol Cell Cardiol. 2018 Aug;121:205-211. (PMID: 30040954); Intern Med. 2006;45(7):429-34. (PMID: 16679696); Mol Pharmacol. 2021 Feb;99(2):104-113. (PMID: 33239332); Stem Cell Reports. 2014 Nov 11;3(5):905-14. (PMID: 25418732); Arch Toxicol. 2015 Sep;89(9):1401-38. (PMID: 25708889); Eur J Pharmacol. 1997 Jan 29;319(2-3):369-73. (PMID: 9042613); Peptides. 1993 Nov-Dec;14(6):1141-7. (PMID: 8134295); J Clin Invest. 2002 Jul;110(2):271-9. (PMID: 12122119); Endocr Rev. 2006 Dec;27(7):736-49. (PMID: 17077189); Front Physiol. 2018 Oct 26;9:1475. (PMID: 30416452); Cell Mol Life Sci. 2015 Apr;72(7):1331-45. (PMID: 25504085); Circulation. 2022 Feb 22;145(8):e153-e639. (PMID: 35078371); Biochem Biophys Res Commun. 2008 May 30;370(2):274-8. (PMID: 18375200); Biochemistry. 1994 Apr 19;33(15):4543-9. (PMID: 8161509); Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1346-54. (PMID: 24790139); Cardiovasc Res. 1995 Oct;30(4):537-43. (PMID: 8575002) |
| Grant Information: | 315351; 266621; 321564; 333284 Research Council of Finland (AKA); GM-104080 HHS | National Institutes of Health (NIH) |
| Contributed Indexing: | Keywords: Fibrosis; Heart Failure; Hypertrophy; Melanocortin Receptor; Melanocyte-stimulating Hormone |
| Substance Nomenclature: | 581-05-5 (alpha-MSH); 0 (melanocortin 5 receptor); 0 (Receptors, Corticotropin); 0 (Receptors, Melanocortin) |
| Entry Date(s): | Date Created: 20240307 Date Completed: 20240415 Latest Revision: 20240520 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11014855 |
| DOI: | 10.1038/s44319-024-00109-6 |
| PMID: | 38454158 |
| Database: | MEDLINE |
Journal Article