https://doi.org/10.4081/ejh.2024.4122
Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction
Submitted: 6 August 2024
Accepted: 9 October 2024
Published: 28 October 2024
Accepted: 9 October 2024
Abstract Views: 304
PDF: 113
HTML: 0
HTML: 0
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Heart failure with preserved ejection fraction (HFpEF), a complex disease that is increasingly prevalent due to population aging, pose significant challenges in its treatment. The present study utilized the HFpEF rat model and H9C2 cells as research subjects to thoroughly investigate the potential mechanisms of alarin in protecting cardiac function in HFpEF. The study shows that under HFpEF conditions, oxidative stress significantly increases, leading to myocardial structural damage and dysfunction of calcium ion channels, which ultimately impairs diastolic function. Alarin, through its interaction with NADPH oxidase 1 (NOX1), effectively alleviates oxidative stress and modulates the activities of type 2 ryanodine receptor (RyR2) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), thereby facilitating the restoration of Ca2+ homeostasis and significantly improving cardiac function in the HFpEF model. This research not only uncovers the cardioprotective effects of alarin and its underlying molecular mechanisms but also provides new insights and potential therapeutic targets for HFpEF treatment strategies, suggesting a promising future for alarin and related therapies in the management of this debilitating condition.
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726.
DOI: https://doi.org/10.1093/eurheartj/ehab368
Pagel PS, Tawil JN, Boettcher BT, Izquierdo DA, Lazicki TJ, Crystal GJ et al. Heart failure with preserved ejection fraction: A comprehensive review and update of diagnosis, pathophysiology, treatment, and perioperative implications. J Cardiothorac Vasc Anesth 2021;35:1839-59.
DOI: https://doi.org/10.1053/j.jvca.2020.07.016
Dal Canto E, Remmelzwaal S, van Ballegooijen AJ, Handoko ML, Heymans S, van Empel V et al. Diagnostic value of echocardiographic markers for diastolic dysfunction and heart failure with preserved ejection fraction. Heart Fail Rev 2022;27:207-18.
DOI: https://doi.org/10.1007/s10741-020-09985-1
Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2021;18:400-23.
DOI: https://doi.org/10.1038/s41569-020-00480-6
Goldstein D, Frishman WH. Diastolic heart failure: a review of current and future treatment options. Cardiol Rev 2021;29:82-8.
DOI: https://doi.org/10.1097/CRD.0000000000000303
Sag CM, Santos CX, Shah AM. Redox regulation of cardiac hypertrophy. J Mol Cell Cardiol 2014;73:103-11.
DOI: https://doi.org/10.1016/j.yjmcc.2014.02.002
Madamanchi NR, Runge MS. Redox signaling in cardiovascular health and disease. Free Radic Biol Med 2013;61:473-501.
DOI: https://doi.org/10.1016/j.freeradbiomed.2013.04.001
Aramouni K, Assaf R, Shaito A, Fardoun M, Al-Asmakh M, Sahebkar A et al. Biochemical and cellular basis of oxidative stress: Implications for disease onset. J Cell Physiol 2023;238:1951-63.
DOI: https://doi.org/10.1002/jcp.31071
Shaito A, Aramouni K, Assaf R, Parenti A, Orekhov A, Yazbi AE et al. Oxidative stress-induced endothelial dysfunction in cardiovascular diseases. Front Biosci (Landmark Ed) 2022;27:105.
DOI: https://doi.org/10.31083/j.fbl2703105
Shi L, Fu W, Xu H, Li S, Yang X, Yang W et al. Ginsenoside Rc attenuates myocardial ischaemic injury through antioxidative and anti-inflammatory effects. Pharm Biol 2022;60:1038-46.
DOI: https://doi.org/10.1080/13880209.2022.2072518
Buvelot H, Jaquet V, Krause KH. Mammalian NADPH Oxidases. Methods Mol Biol 2019;1982:17-36.
DOI: https://doi.org/10.1007/978-1-4939-9424-3_2
Meyer MR, Barton M. GPER blockers as Nox downregulators: A new drug class to target chronic non-communicable diseases. J Steroid Biochem Mol Biol 2018;176:82-7.
DOI: https://doi.org/10.1016/j.jsbmb.2017.03.019
Barton M, Meyer MR, Prossnitz ER. Nox1 downregulators: A new class of therapeutics. Steroids 2019;152:108494.
DOI: https://doi.org/10.1016/j.steroids.2019.108494
Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med 2013;63:338-49.
DOI: https://doi.org/10.1016/j.freeradbiomed.2013.05.035
Adachi T, Weisbrod RM, Pimentel DR, Ying J, Sharov VS, Schoneich C et al. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat Med 2004;10:1200-7.
DOI: https://doi.org/10.1038/nm1119
Zhang N, Zhu B. The role of the rat sarcoplasmic reticulum Ca2+-ATPase promoter in myocardial ischemia-preconditioning. Mol Cell Biochem 2010;333:311-21.
DOI: https://doi.org/10.1007/s11010-009-0232-0
Bovo E, Mazurek SR, Zima AV. The role of RyR2 oxidation in the blunted frequency-dependent facilitation of Ca(2+) transient amplitude in rabbit failing myocytes. Pflugers Arch 2018;470:959-68.
DOI: https://doi.org/10.1007/s00424-018-2122-3
Hamilton S, Terentyeva R, Martin B, Perger F, Li J, Stepanov A et al. Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS. Basic Res Cardiol 2020;115:38.
DOI: https://doi.org/10.1007/s00395-020-0797-z
Dridi H, Kushnir A, Zalk R, Yuan Q, Melville Z, Marks AR. Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat Rev Cardiol 2020;17:732-47.
DOI: https://doi.org/10.1038/s41569-020-0394-8
Spertus JA, Birmingham MC, Nassif M, Damaraju CV, Abbate A, Butler J, et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med 2022;28:809-13.
DOI: https://doi.org/10.1038/s41591-022-01703-8
Martin N, Manoharan K, Davies C, Lumbers RT. Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Db Syst Rev 2021;5:CD12721.
DOI: https://doi.org/10.1002/14651858.CD012721.pub3
Lima-Posada I, Stephan Y, Soulie M, Palacios-Ramirez R, Bonnard B, Nicol L, et al. Benefits of the non-steroidal mineralocorticoid receptor antagonist finerenone in metabolic syndrome-related heart failure with preserved ejection fraction. Int J Mol Sci 2023;24:2536.
DOI: https://doi.org/10.3390/ijms24032536
Mills EG, Izzi-Engbeaya C, Abbara A, Comninos AN, Dhillo WS. Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour. Nat Rev Endocrinol 2021;17:97-113.
DOI: https://doi.org/10.1038/s41574-020-00438-1
Rana T, Behl T, Sehgal A, Singh S, Sharma N, Abdeen, A et al. Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2022;114:110478.
DOI: https://doi.org/10.1016/j.pnpbp.2021.110478
Sipkova J, Kramarikova I, Hynie S, Klenerova V. The galanin and galanin receptor subtypes, its regulatory role in the biological and pathological functions. Physiol Res 2017;66:729-40.
DOI: https://doi.org/10.33549/physiolres.933576
Brzozowska M, Calka J. Review: occurrence and distribution of galanin in the physiological and inflammatory states in the mammalian gastrointestinal tract. Front Immunol 2020;11:602070.
DOI: https://doi.org/10.3389/fimmu.2020.602070
Li J, Ding H, Li Y, Zhou H, Wang W, Mei Y, et al. Alarin alleviated cardiac fibrosis via attenuating oxidative stress in heart failure rats. Amino Acids 2021;53:1079-89.
DOI: https://doi.org/10.1007/s00726-021-03005-8
Abebe EC, Mengstie MA, Seid MA, Malik T, Dejenie TA. The evolving roles of alarin in physiological and disease conditions, and its future potential clinical implications. Front Endocrinol (Lausanne) 2022;13:1028982.
DOI: https://doi.org/10.3389/fendo.2022.1028982
Sorimachi H, Burkhoff D, Verbrugge FH, Omote K, Obokata M, Reddy YNV, et al. Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23:1648-58.
DOI: https://doi.org/10.1002/ejhf.2254
Packer M, Lam CSP, Lund LH, Maurer MS, Borlaug BA. Characterization of the inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease. Eur J Heart Fail 2020;22:1551-67.
DOI: https://doi.org/10.1002/ejhf.1902
Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS, Wagner PD, et al. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O(2) pathway analysis. Circulation 2018;137:148-61.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.029058
Monma Y, Shindo T, Eguchi K, Kurosawa R, Kagaya Y, Ikumi Y, et al. Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction. Cardiovasc Res 2021;117:1325-38.
DOI: https://doi.org/10.1093/cvr/cvaa221
Triposkiadis F, Xanthopoulos A, Starling RC, Iliodromitis E. Obesity, inflammation, and heart failure: links and misconceptions. Heart Fail Rev 2022;27:407-18.
DOI: https://doi.org/10.1007/s10741-021-10103-y
Eisner DA, Caldwell JL, Kistamas K, Trafford AW. Calcium and excitation-contraction coupling in the heart. Circ Res 2017;121:181-95.
DOI: https://doi.org/10.1161/CIRCRESAHA.117.310230
Santic R SS, Lang R, Rauch I, Voglas E, Eberhard N, Bauer JW, Brain SD, Kofler B. Alarin is a vasoactive peptide. Proc Natl Acad Sci USA 2007;104:10217-22.
DOI: https://doi.org/10.1073/pnas.0608585104
Kura B, Szeiffova Bacova B, Kalocayova B, Sykora M, Slezak J. Oxidative stress-responsive microRNAs in heart injury. Int J Mol Sci 2020;21:358.
DOI: https://doi.org/10.3390/ijms21010358
Zhang Y, Murugesan P, Huang K, Cai H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat Rev Cardiol 2020;17:170-94.
DOI: https://doi.org/10.1038/s41569-019-0260-8
Kilinc F, Demircan F, Gozel N, Onalan E, Karatas A, Pekkolay Z, et al. Assessment of serum alarin levels in patients with type 2 diabetes mellitus. Acta Endocrinol-Buch 2020;16:165-9.
DOI: https://doi.org/10.4183/aeb.2020.165
Zhou X, Luo M, Zhou S, Cheng Z, Chen Z, Yu X. plasma alarin level and its influencing factors in obese newly diagnosed type 2 diabetes patients. Diabet Metab Synd Ob 2021;14:379-85.
DOI: https://doi.org/10.2147/DMSO.S290072
Ethics Approval
the experiments on rats were approved by the Experimental Animal Care and Use Committee of Xuzhou Medical UniversitySupporting Agencies
Suqian Sci&Tech Program, Suqian Traditional Chinese Medicine Technology Program, Xuzhou Medical University Affiliated Hospital Sci&Tech ProgramHow to Cite
Li, J., Xu, D., Shi, C., Cheng, C., Xu, Z., Gao, X., & Cheng, Y. (2024). Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction. European Journal of Histochemistry, 68(4). https://doi.org/10.4081/ejh.2024.4122
Copyright (c) 2024 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Valentina Alda Carozzi, Chiara Salio, Virginia Rodriguez-Menendez, Elisa Ciglieri, Francesco Ferrini, 2D vs 3D morphological analysis of dorsal root ganglia in health and painful neuropathy , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
- Jacopo J.V. Branca, Donatello Carrino, Ferdinando Paternostro, Massimo Gulisano, Matteo Becatti, Lorenzo Di Cesare Mannelli, Alessandra Pacini, Antioxidant support to ameliorate the oxaliplatin-dependent microglial alteration: morphological and molecular study , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
- Tadashi Yasui, Hiroshi Gomi, Taishi Kitahara, Azuma Tsukise, Ultrastructure and immunohistochemical characterization of proteins concerned with the secretory machinery in goat ceruminous glands , European Journal of Histochemistry: Vol. 61 No. 3 (2017)
- A.C. Croce, G. Bottiroli, Autofluorescence spectroscopy and imaging: a tool for biomedical research and diagnosis , European Journal of Histochemistry: Vol. 58 No. 4 (2014)
- S. Ćirović, J. Marković-Lipkovski, J. Todorović, J. Nešović-Ostojić, M. Jović, S. Ilić, S. Tatić, D. Čemerikić, Differential expression of KCNQ1 K+ channel in tubular cells of frog kidney , European Journal of Histochemistry: Vol. 54 No. 1 (2010)
- Chiara Rita Inguscio, Flavia Carton, Barbara Cisterna, Manuela Rizzi, Francesca Boccafoschi, Gabriele Tabaracci, Manuela Malatesta, Low ozone concentrations do not exert cytoprotective effects on tamoxifen-treated breast cancer cells in vitro , European Journal of Histochemistry: Vol. 68 No. 3 (2024)
- F. Frontalini, D. Curzi, F.M. Giordano, J.M. Bernhard, E. Falcieri, R. Coccioni, Effects of lead pollution on Ammonia parkinsoniana (foraminifera): ultrastructural and microanalytical approaches , European Journal of Histochemistry: Vol. 59 No. 1 (2015)
- I. N. Vatsos, Y. Kotzamanis, M. Henry, P. Angelidis, M. Alexis, Monitoring stress in fish by applying image analysis to their skin mucous cells , European Journal of Histochemistry: Vol. 54 No. 2 (2010)
- Arturo Mangas, Javier Yajeya, Noelia González, Isabel Ruiz, Marianny Pernía, Michel Geffard, Rafael Coveñas, Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke , European Journal of Histochemistry: Vol. 61 No. 2 (2017)
- E. Negrato, M. Vascellari, F. Capolongo, G. Binato, L. Da Dalt, M. Boscolo Papo, G. Gioacchini, O. Carnevali, D. Bertotto, G. Radaelli, F. Pascoli, Expression of 8-OHdG in Zosterisessor ophiocephalus from the Venetian lagoon, Italy , European Journal of Histochemistry: Vol. 57 No. 1 (2013)
<< < 1 2 3 4 5 6 7 8 9 10 > >>
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
3
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
82
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
