Triggered Ca²⁺-dependent mechanism of early age-related impairments in cardiac contractile function in male and female rats
Keywords:
aging, sexual dimorphism, expression, heart, ryanodine receptors, RyR2, inositol-145-trisphosphate receptors, IP3R, calmodulin, Epac2, CaV1.2 KV1.1 1.3 1.6 каналы, SERCA2, phospholamban
Abstract
Age-related structural and functional changes in the heart are diagnosed earlier in males than in females. The mechanisms underlying sex differences in age-associated electrical instability and impaired myocardial contractility remain insufficiently studied. Aim: To investigate sex-specific age-related changes in the transcriptional activity of genes encoding key proteins maintaining electrical stability and myocardial contractility—CaV1.2, KV1 channels, IP3R and RyR2 receptors, and regulatory proteins SERCA2, phospholamban , calmodulin, and Epac2. Materials and Methods: The study was conducted on male and female Wistar rats aged 4 and 18 months. Using PCR analysis, gene expression of the aforementioned proteins was evaluated in the atria and left ventricle of young and aged rats. Results: In male rats, aging was associated with more pronounced disruptions in calcium-handling proteins compared to females. In aged males, significant upregulation of genes encoding voltage-gated CaV1.2 and KV1.1 channels, ryanodine RyR2 receptors, inositol trisphosphate IP3R1, IP3R2, IP3R3 receptors, and their regulators—calmodulin, Epac2, sarcoplasmic Ca²⁺-ATPase (SERCA2), and phospholamban—was observed in the left ventricle and atria. In females, age-related gene expression changes in the left ventricle were minimal, with only increased mRNA levels of Epac2 and CaM, and reduced RyR2 and IP3R3. Major deviations from young females were detected in the atria, particularly the right atrium: hyperexpression of KV1.1 and CaV1.2 channels, RyR2, IP3R1, IP3R3 receptors, and Epac2, CaM proteins. Both sexes showed marked reduction in KV1.6 channel mRNA levels. Conclusion: Age-related disruptions in cardiac rhythm and myocardial contractility are proposed to be triggered by altered transcriptional activity of genes regulating calcium homeostasis and electrical myocardial activity. These changes are more pronounced in males.
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References
1. Lakatta E.G. So! What's aging? Is cardiovascular aging a disease? J. Mol. Cell Cardiol. 2015; 83: 1–13. https://doi.org/10.1016/j.yjmcc.2015.04.005
2. Chen M.S., Lee R.T., Garbern J.C. Senescence mechanisms and targets in the heart. Cardiovasc. Res. 2022; 118(5): 1173–1187. https://doi.org/10.1093/cvr/cvab161
3. Maldonado E., Morales-Pison S., Urbina F., Solari A. Aging Hallmarks and the Role of Oxidative Stress. Antioxidants (Basel) 2023; 12(3): 651. https://doi.org/10.3390/antiox12030651
4. Vijayakumar A., Wang M., Kailasam S. The Senescent Heart—"Age Doth Wither Its Infinite Variety". Int. J. Mol. Sci. 2024; 25(7): 3581. https://doi.org/10.3390/ijms25073581
5. Prajapati C., Koivumäki J., Pekkanen-Mattila M., Aalto-Setälä K. Sex differences in heart: from basics to clinics. Eur. J. Med. Res. 2022; 27(1): 241. https://doi.org/10.1186/s40001-022-00880-z
6. Cannatà A., Fabris E., Merlo M., Artico J., Gentile P., Pio Loco C., Ballaben A., Ramani F., Barbati G., Sinagra G. Sex Differences in the Long-term Prognosis of Dilated Cardiomyopathy. Can. J. Cardiol. 2020; 36(1): 37–44. https://doi.org/10.1016/j.cjca.2019.05.031
7. Kavousi M. Differences in Epidemiology and Risk Factors for Atrial Fibrillation Between Women and Men. Front. Cardiovasc. Med. 2020; 7: 3. https://doi.org/10.3389/fcvm.2020.00003
8. Qian N., Jin J., Gao Y., Liu J., Wang Y. Sex Differences in Atrial Fibrillation: Evidence from Circulating Metabolites. Metabolites 2025; 15(3): 170. https://doi.org/10.3390/metabo15030170
9. Karamnov S., Sarkisian N., Wollborn J., Justice S., Fields K., Kovacheva V.P., Osho A.A., Sabe A., Body S.C., Muehlschlegel J.D. Sex, Atrial Fibrillation, and Long-Term Mortality After Cardiac Surgery. JAMA Netw. Open 2024; 7(8): e2426865. https://doi.org/10.1001/jamanetworkopen.2024.26865
10. Tsuneda T., Yamashita T., Kato T., Sekiguchi A., Sagara K., Sawada H., Aizawa T., Fu L.T., Fujiki A., Inoue H. Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. J. Cardiovasc. Electrophysiol. 2009; 20(9): 1055–1060. https://doi.org/10.1111/j.1540-8167.2009.01474.x
11. Tykocki N.R., Boerman E.M., Jackson W.F. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr. Physiol. 2017; 7(2): 485–581. https://doi.org/10.1002/cphy.c160011
12. Garcia M.I., Karlstaedt A., Chen J.J., Amione-Guerra J., Youker K.A., Taegtmeyer H., Boehning D. Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors. J. Mol. Cell Cardiol. 2017; 112: 95–103. https://doi.org/10.1016/j.yjmcc.2017.09.006
13. Dulhunty A.F., Beard N.A., Casarotto M.G. Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling. F1000Res. 2018; 7: F1000 Faculty Rev-1851. https://doi.org/10.12688/f1000research.16434.1
14. Mangla A., Guerra M.T., Nathanson M.H. Type 3 inositol 1,4,5-trisphosphate receptor: A calcium channel for all seasons. Cell Calcium 2020; 85: 102132. https://doi.org/10.1016/j.ceca.2019.102132
15. Demydenko K., Ekhteraei-Tousi S., Roderick H.L. Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2022; 377(1864): 20210319. https://doi.org/10.1098/rstb.2021.0319
16. Chen M.S., Lee R.T., Garbern J.C. Senescence mechanisms and targets in the heart. Cardiovasc. Res. 2022; 118(5): 1173–1187. https://doi.org/10.1093/cvr/cvab161
17. Seo M.D., Enomoto M., Ishiyama N., Stathopulos P.B., Ikura M. Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim. Biophys. Acta 2015; 1853(9): 1980–1991. https://doi.org/10.1016/j.bbamcr.2014.11.023
18. Dixon R.E. Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels. Front. Physiol. 2022; 12: 810408. https://doi.org/10.3389/fphys.2021.810408
19. Lee L.C., Maurice D.H., Baillie G.S. Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Med. Chem. 2013; 5(4): 451–464. https://doi.org/10.4155/fmc.12.216
20. de Lucia C., Eguchi A., Koch W.J. New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging. Front. Pharmacol. 2018; 9: 904. https://doi.org/10.3389/fphar.2018.00904
21. Hamilton S., Terentyev D. Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart. Int. J. Mol. Sci. 2019; 20(10): 2386. https://doi.org/10.3390/ijms20102386
22. Federico M., Valverde C.A., Mattiazzi A., Palomeque J. Unbalance Between Sarcoplasmic Reticulum Ca²⁺ Uptake and Release: A First Step Toward Ca²⁺ Triggered Arrhythmias and Cardiac Damage. Front. Physiol. 2020; 10: 1630. https://doi.org/10.3389/fphys.2019.01630
23. Herold K.G., Hussey J.W., Dick I.E. CACNA1C-Related Channelopathies. Handb. Exp. Pharmacol. 2023; 279: 159–181. https://doi.org/10.1007/164_2022_624
24. Woodcock E.A., Matkovich S.J. Ins(1,4,5)P3 receptors and inositol phosphates in the heart—evolutionary artefacts or active signal transducers? Pharmacol. Ther. 2005; 107(2): 240–251. https://doi.org/10.1016/j.pharmthera.2005.04.002
25. Trosclair K., Si M., Watts M., Gautier N.M., Voigt N., Traylor J., Bitay M., Baczko I., Dobrev D., Hamilton K.A., Bhuiyan M.S., Dominic P., Glasscock E. Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization. Physiol. Rep. 2021; 9(1): e14702. https://doi.org/10.14814/phy2.14702
26. Dwenger M.M., Raph S.M., Baba S.P., Moore J.B. 4th, Nystoriak M.A. Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins. Cells. 2022; 11(14): 2230. https://doi.org/10.3390/cells11142230
27. Bähring R., Vardanyan V., Pongs O. Differential modulation of Kv1 channel-mediated currents by co-expression of Kvβ3 subunit in a mammalian cell-line. Mol. Membr. Biol. 2004; 21(1): 19–25. https://doi.org/10.1080/09687680310001597749
28. Si M., Darvish A., Paulhus K., Kumar P., Hamilton K.A., Glasscock E. Epilepsy-associated Kv1.1 channel subunits regulate intrinsic cardiac pacemaking in mice. J. Gen. Physiol. 2024; 156(9): e202413578. https://doi.org/10.1085/jgp.202413578
29. Weisleder N., Ma J. Altered Ca²⁺ sparks in aging skeletal and cardiac muscle. Ageing Res. Rev. 2008; 7(3): 177–188. https://doi.org/10.1016/j.arr.2007.12.003
30. Marx S.O., Marks A.R. Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J. Mol. Cell Cardiol. 2013; 58: 225–231. https://doi.org/10.1016/j.yjmcc.2013.03.005
31. Urrutia J., Aguado A., Muguruza-Montero A., Núñez E., Malo C., Casis O., Villarroel A. The Crossroad of Ion Channels and Calmodulin in Disease. Int. J. Mol. Sci. 2019; 20(2): 400. https://doi.org/10.3390/ijms20020400
32. Zhou X., Sun F., Luo S., Zhao W., Yang T., Zhang G., Gao M., Lu R., Shu Y., Mu W., Zhuang Y., Ding F., Xu C., Lu Y. Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin. Int. J. Biol. Sci. 2017; 13(1): 22–31. https://doi.org/10.7150/ijbs.16298
33. Arnáiz-Cot J.J., Damon B.J., Zhang X.H., Cleemann L., Yamaguchi N., Meissner G., Morad M. Cardiac calcium signalling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor. J. Physiol. 2013; 591(17): 4287–4299. https://doi.org/10.1113/jphysiol.2013.256123
34. Kozhevnikova L.M., Tsorin I.B., Stolyaruk V.N., Sukhanova I.F., Vititnova M.B., Nikiforova T.D., Kolik L.G., Kryzhanovskii S.A. Epac Proteins and Calmodulin as Possible Arrhythmogenesis Trigger in Alcoholic Cardiomyopathy. Bull. Exp. Biol. Med. 2018; 165(5): 613–616. https://doi.org/10.1007/s10517-018-4225-4
35. Ruiz-Hurtado G., Morel E., Domínguez-Rodríguez A., Llach A., Lezoualc'h F., Benitah J.P., Gomez A.M. Epac in cardiac calcium signaling. J. Mol. Cell Cardiol. 2013; 58: 162–171. https://doi.org/10.1016/j.yjmcc.2012.11.021
36. Lipp P., Laine M., Tovey S.C., Burrell K.M., Berridge M.J., Li W., Bootman M.D. Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart. Curr. Biol. 2000; 10(15): 939–942. https://doi.org/10.1016/s0960-9822 (00)00624-2
37. Kockskämper J., Zima A.V., Roderick H.L., Pieske B., Blatter L.A., Bootman M.D. Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes. J. Mol. Cell Cardiol. 2008; 45(2): 128–147. https://doi.org/10.1016/j.yjmcc.2008.05.014
38. Kim J.C., Son M.J., Subedi K.P., Li Y., Ahn J.R., Woo S.H. Atrial local Ca²⁺ signaling and inositol 1,4,5-trisphosphate receptors. Prog. Biophys. Mol. Biol. 2010; 103(1): 59–70. https://doi.org/10.1016/j.pbiomolbio.2010.02.002
39. Ju Y.K., Woodcock E.A., Allen D.G., Cannell M.B. Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms. J. Mol. Cell Cardiol. 2012; 53(3): 375–381. https://doi.org/10.1016/j.yjmcc.2012.06.004
40. Wu X., Zhang T., Bossuyt J., Li X., McKinsey T.A., Dedman J.R., Olson E.N., Chen J., Brown J.H., Bers D.M. Local InsP3-dependent perinuclear Ca²⁺ signaling in cardiac myocyte excitation-transcription coupling. J. Clin. Invest. 2006; 116(3): 675–682. https://doi.org/10.1172/JCI27374
41. Ljubojevic S., Bers D.M. Nuclear calcium in cardiac myocytes. J. Cardiovasc. Pharmacol. 2015; 65(3): 211–217. https://doi.org/10.1097/FJC.0000000000000174
42. Zima A.V., Bare D.J., Mignery G.A., Blatter L.A. IP3-dependent nuclear Ca²⁺ signalling in the mammalian heart. J. Physiol. 2007; 584(Pt 2): 601–611. https://doi.org/10.1113/jphysiol.2007.140731
43. Kockskämper J., Seidlmayer L., Walther S., Hellenkamp K., Maier L.S., Pieske B. Endothelin-1 enhances nuclear Ca²⁺ transients in atrial myocytes through Ins(1,4,5)P3-dependent Ca²⁺ release from perinuclear Ca²⁺ stores. J. Cell Sci. 2008; 121(Pt 2): 186–195. https://doi.org/10.1242/jcs.021386
44. Yamda J., Ohkusa T., Nao T., Ueyama T., Yano M., Kobayashi S., Hamano K., Esato K., Matsuzaki M. Up-regulation of inositol 1,4,5-trisphosphate receptor expression in atrial tissue in patients with chronic atrial fibrillation. J. Am. Coll. Cardiol. 2001; 37(4): 1111–1119. https://doi.org/10.1016/s0735-1097 (01)01144-5
45. Liang X., Xie H., Zhu P.H., Hu J., Zhao Q., Wang C.S., Yang C. Enhanced activity of inositol-1,4,5-trisphosphate receptors in atrial myocytes of atrial fibrillation patients. Cardiology 2009; 114(3): 180–191. https://doi.org/10.1159/000228584
46. Hattori M., Suzuki A.Z., Higo T., Miyauchi H., Michikawa T., Nakamura T., Inoue T., Mikoshiba K. Distinct roles of inositol 1,4,5-trisphosphate receptor types 1 and 3 in Ca²⁺ signaling. J. Biol. Chem. 2004; 279(12): 11967–11975. https://doi.org/10.1074/jbc.m311456200
47. Belke D.D., Swanson E., Suarez J., Scott B.T., Stenbit A.E., Dillmann W.H. Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose. Am. J. Physiol. Heart Circ. Physiol. 2007; 292(4): H1755–H1763. https://doi.org/10.1152/ajpheart.00884.2006
48. Gambardella J., Trimarco B., Iaccarino G., Santulli G. New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling. Adv. Exp. Med. Biol. 2018; 1067: 373–385. https://doi.org/10.1007/5584_2017_106
49. Gonnot F., Boulogne L., Brun C., Dia M., Gouriou Y., Bidaux G., Chouabe C., Crola Da Silva C., Ducreux S., Pillot B., Kaczmarczyk A., Leon C., Chanon S., Perret C., Sciandra F., Dargar T., Gache V., Farhat F., Sebbag L., Bochaton T., Thibault H., Ovize M., Paillard M., Gomez L. SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases. Nat. Commun. 2023; 14(1): 3346. https://doi.org/10.1038/s41467-023-39027-x
50. Liu Y.B., Wang Q., Song Y.L., Song X.M., Fan Y.C., Kong L., Zhang J.S., Li S., Lv Y.J., Li Z.Y., Dai J.Y., Qiu Z.K. Abnormal phosphorylation / dephosphorylation and Ca²⁺ dysfunction in heart failure. Heart Fail. Rev. 2024; 29(4): 751–768. https://doi.org/10.1007/s10741-024-10395-w
51. Bencurova M., Lysikova T., Leskova Majdova K., Kaplan P., Racay P., Lehotsky J., Tatarkova Z. Age-Dependent Changes in Calcium Regulation after Myocardial Ischemia-Reperfusion Injury. Biomedicines 2023; 11(4): 1193. https://doi.org/10.3390/biomedicines11041193
52. Hamilton S., Terentyev D. Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart. Int. J. Mol. Sci. 2019; 20(10): 2386. https://doi.org/10.3390/ijms20102386
53. Del Monte F., Hajjar R.J. Intracellular devastation in heart failure. Heart Fail. Rev. 2008; 13(2): 151–162. https://doi.org/10.1007/s10741-007-9071-9
54. MacLennan D.H., Kranias E.G. Phospholamban: a crucial regulator of cardiac contractility. Nat. Rev. Mol. Cell Biol. 2003; 4(7): 566–577. https://doi.org/10.1038/nrm1151
55. Ragone I., Barallobre-Barreiro J., Takov K., Theofilatos K., Yin X., Schmidt L.E., Domenech N., Crespo-Leiro M.G., van der Voorn S.M., Vink A., van Veen T.A.B., Bödör C., Merkely B., Radovits T., Mayr M. SERCA2a Protein Levels Are Unaltered in Human Heart Failure. Circulation 2023; 148(7): 613–616. https://doi.org/10.1161/CIRCULATIONAHA.123.064513
2. Chen M.S., Lee R.T., Garbern J.C. Senescence mechanisms and targets in the heart. Cardiovasc. Res. 2022; 118(5): 1173–1187. https://doi.org/10.1093/cvr/cvab161
3. Maldonado E., Morales-Pison S., Urbina F., Solari A. Aging Hallmarks and the Role of Oxidative Stress. Antioxidants (Basel) 2023; 12(3): 651. https://doi.org/10.3390/antiox12030651
4. Vijayakumar A., Wang M., Kailasam S. The Senescent Heart—"Age Doth Wither Its Infinite Variety". Int. J. Mol. Sci. 2024; 25(7): 3581. https://doi.org/10.3390/ijms25073581
5. Prajapati C., Koivumäki J., Pekkanen-Mattila M., Aalto-Setälä K. Sex differences in heart: from basics to clinics. Eur. J. Med. Res. 2022; 27(1): 241. https://doi.org/10.1186/s40001-022-00880-z
6. Cannatà A., Fabris E., Merlo M., Artico J., Gentile P., Pio Loco C., Ballaben A., Ramani F., Barbati G., Sinagra G. Sex Differences in the Long-term Prognosis of Dilated Cardiomyopathy. Can. J. Cardiol. 2020; 36(1): 37–44. https://doi.org/10.1016/j.cjca.2019.05.031
7. Kavousi M. Differences in Epidemiology and Risk Factors for Atrial Fibrillation Between Women and Men. Front. Cardiovasc. Med. 2020; 7: 3. https://doi.org/10.3389/fcvm.2020.00003
8. Qian N., Jin J., Gao Y., Liu J., Wang Y. Sex Differences in Atrial Fibrillation: Evidence from Circulating Metabolites. Metabolites 2025; 15(3): 170. https://doi.org/10.3390/metabo15030170
9. Karamnov S., Sarkisian N., Wollborn J., Justice S., Fields K., Kovacheva V.P., Osho A.A., Sabe A., Body S.C., Muehlschlegel J.D. Sex, Atrial Fibrillation, and Long-Term Mortality After Cardiac Surgery. JAMA Netw. Open 2024; 7(8): e2426865. https://doi.org/10.1001/jamanetworkopen.2024.26865
10. Tsuneda T., Yamashita T., Kato T., Sekiguchi A., Sagara K., Sawada H., Aizawa T., Fu L.T., Fujiki A., Inoue H. Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. J. Cardiovasc. Electrophysiol. 2009; 20(9): 1055–1060. https://doi.org/10.1111/j.1540-8167.2009.01474.x
11. Tykocki N.R., Boerman E.M., Jackson W.F. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr. Physiol. 2017; 7(2): 485–581. https://doi.org/10.1002/cphy.c160011
12. Garcia M.I., Karlstaedt A., Chen J.J., Amione-Guerra J., Youker K.A., Taegtmeyer H., Boehning D. Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors. J. Mol. Cell Cardiol. 2017; 112: 95–103. https://doi.org/10.1016/j.yjmcc.2017.09.006
13. Dulhunty A.F., Beard N.A., Casarotto M.G. Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling. F1000Res. 2018; 7: F1000 Faculty Rev-1851. https://doi.org/10.12688/f1000research.16434.1
14. Mangla A., Guerra M.T., Nathanson M.H. Type 3 inositol 1,4,5-trisphosphate receptor: A calcium channel for all seasons. Cell Calcium 2020; 85: 102132. https://doi.org/10.1016/j.ceca.2019.102132
15. Demydenko K., Ekhteraei-Tousi S., Roderick H.L. Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2022; 377(1864): 20210319. https://doi.org/10.1098/rstb.2021.0319
16. Chen M.S., Lee R.T., Garbern J.C. Senescence mechanisms and targets in the heart. Cardiovasc. Res. 2022; 118(5): 1173–1187. https://doi.org/10.1093/cvr/cvab161
17. Seo M.D., Enomoto M., Ishiyama N., Stathopulos P.B., Ikura M. Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim. Biophys. Acta 2015; 1853(9): 1980–1991. https://doi.org/10.1016/j.bbamcr.2014.11.023
18. Dixon R.E. Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels. Front. Physiol. 2022; 12: 810408. https://doi.org/10.3389/fphys.2021.810408
19. Lee L.C., Maurice D.H., Baillie G.S. Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Med. Chem. 2013; 5(4): 451–464. https://doi.org/10.4155/fmc.12.216
20. de Lucia C., Eguchi A., Koch W.J. New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging. Front. Pharmacol. 2018; 9: 904. https://doi.org/10.3389/fphar.2018.00904
21. Hamilton S., Terentyev D. Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart. Int. J. Mol. Sci. 2019; 20(10): 2386. https://doi.org/10.3390/ijms20102386
22. Federico M., Valverde C.A., Mattiazzi A., Palomeque J. Unbalance Between Sarcoplasmic Reticulum Ca²⁺ Uptake and Release: A First Step Toward Ca²⁺ Triggered Arrhythmias and Cardiac Damage. Front. Physiol. 2020; 10: 1630. https://doi.org/10.3389/fphys.2019.01630
23. Herold K.G., Hussey J.W., Dick I.E. CACNA1C-Related Channelopathies. Handb. Exp. Pharmacol. 2023; 279: 159–181. https://doi.org/10.1007/164_2022_624
24. Woodcock E.A., Matkovich S.J. Ins(1,4,5)P3 receptors and inositol phosphates in the heart—evolutionary artefacts or active signal transducers? Pharmacol. Ther. 2005; 107(2): 240–251. https://doi.org/10.1016/j.pharmthera.2005.04.002
25. Trosclair K., Si M., Watts M., Gautier N.M., Voigt N., Traylor J., Bitay M., Baczko I., Dobrev D., Hamilton K.A., Bhuiyan M.S., Dominic P., Glasscock E. Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization. Physiol. Rep. 2021; 9(1): e14702. https://doi.org/10.14814/phy2.14702
26. Dwenger M.M., Raph S.M., Baba S.P., Moore J.B. 4th, Nystoriak M.A. Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins. Cells. 2022; 11(14): 2230. https://doi.org/10.3390/cells11142230
27. Bähring R., Vardanyan V., Pongs O. Differential modulation of Kv1 channel-mediated currents by co-expression of Kvβ3 subunit in a mammalian cell-line. Mol. Membr. Biol. 2004; 21(1): 19–25. https://doi.org/10.1080/09687680310001597749
28. Si M., Darvish A., Paulhus K., Kumar P., Hamilton K.A., Glasscock E. Epilepsy-associated Kv1.1 channel subunits regulate intrinsic cardiac pacemaking in mice. J. Gen. Physiol. 2024; 156(9): e202413578. https://doi.org/10.1085/jgp.202413578
29. Weisleder N., Ma J. Altered Ca²⁺ sparks in aging skeletal and cardiac muscle. Ageing Res. Rev. 2008; 7(3): 177–188. https://doi.org/10.1016/j.arr.2007.12.003
30. Marx S.O., Marks A.R. Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J. Mol. Cell Cardiol. 2013; 58: 225–231. https://doi.org/10.1016/j.yjmcc.2013.03.005
31. Urrutia J., Aguado A., Muguruza-Montero A., Núñez E., Malo C., Casis O., Villarroel A. The Crossroad of Ion Channels and Calmodulin in Disease. Int. J. Mol. Sci. 2019; 20(2): 400. https://doi.org/10.3390/ijms20020400
32. Zhou X., Sun F., Luo S., Zhao W., Yang T., Zhang G., Gao M., Lu R., Shu Y., Mu W., Zhuang Y., Ding F., Xu C., Lu Y. Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin. Int. J. Biol. Sci. 2017; 13(1): 22–31. https://doi.org/10.7150/ijbs.16298
33. Arnáiz-Cot J.J., Damon B.J., Zhang X.H., Cleemann L., Yamaguchi N., Meissner G., Morad M. Cardiac calcium signalling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor. J. Physiol. 2013; 591(17): 4287–4299. https://doi.org/10.1113/jphysiol.2013.256123
34. Kozhevnikova L.M., Tsorin I.B., Stolyaruk V.N., Sukhanova I.F., Vititnova M.B., Nikiforova T.D., Kolik L.G., Kryzhanovskii S.A. Epac Proteins and Calmodulin as Possible Arrhythmogenesis Trigger in Alcoholic Cardiomyopathy. Bull. Exp. Biol. Med. 2018; 165(5): 613–616. https://doi.org/10.1007/s10517-018-4225-4
35. Ruiz-Hurtado G., Morel E., Domínguez-Rodríguez A., Llach A., Lezoualc'h F., Benitah J.P., Gomez A.M. Epac in cardiac calcium signaling. J. Mol. Cell Cardiol. 2013; 58: 162–171. https://doi.org/10.1016/j.yjmcc.2012.11.021
36. Lipp P., Laine M., Tovey S.C., Burrell K.M., Berridge M.J., Li W., Bootman M.D. Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart. Curr. Biol. 2000; 10(15): 939–942. https://doi.org/10.1016/s0960-9822 (00)00624-2
37. Kockskämper J., Zima A.V., Roderick H.L., Pieske B., Blatter L.A., Bootman M.D. Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes. J. Mol. Cell Cardiol. 2008; 45(2): 128–147. https://doi.org/10.1016/j.yjmcc.2008.05.014
38. Kim J.C., Son M.J., Subedi K.P., Li Y., Ahn J.R., Woo S.H. Atrial local Ca²⁺ signaling and inositol 1,4,5-trisphosphate receptors. Prog. Biophys. Mol. Biol. 2010; 103(1): 59–70. https://doi.org/10.1016/j.pbiomolbio.2010.02.002
39. Ju Y.K., Woodcock E.A., Allen D.G., Cannell M.B. Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms. J. Mol. Cell Cardiol. 2012; 53(3): 375–381. https://doi.org/10.1016/j.yjmcc.2012.06.004
40. Wu X., Zhang T., Bossuyt J., Li X., McKinsey T.A., Dedman J.R., Olson E.N., Chen J., Brown J.H., Bers D.M. Local InsP3-dependent perinuclear Ca²⁺ signaling in cardiac myocyte excitation-transcription coupling. J. Clin. Invest. 2006; 116(3): 675–682. https://doi.org/10.1172/JCI27374
41. Ljubojevic S., Bers D.M. Nuclear calcium in cardiac myocytes. J. Cardiovasc. Pharmacol. 2015; 65(3): 211–217. https://doi.org/10.1097/FJC.0000000000000174
42. Zima A.V., Bare D.J., Mignery G.A., Blatter L.A. IP3-dependent nuclear Ca²⁺ signalling in the mammalian heart. J. Physiol. 2007; 584(Pt 2): 601–611. https://doi.org/10.1113/jphysiol.2007.140731
43. Kockskämper J., Seidlmayer L., Walther S., Hellenkamp K., Maier L.S., Pieske B. Endothelin-1 enhances nuclear Ca²⁺ transients in atrial myocytes through Ins(1,4,5)P3-dependent Ca²⁺ release from perinuclear Ca²⁺ stores. J. Cell Sci. 2008; 121(Pt 2): 186–195. https://doi.org/10.1242/jcs.021386
44. Yamda J., Ohkusa T., Nao T., Ueyama T., Yano M., Kobayashi S., Hamano K., Esato K., Matsuzaki M. Up-regulation of inositol 1,4,5-trisphosphate receptor expression in atrial tissue in patients with chronic atrial fibrillation. J. Am. Coll. Cardiol. 2001; 37(4): 1111–1119. https://doi.org/10.1016/s0735-1097 (01)01144-5
45. Liang X., Xie H., Zhu P.H., Hu J., Zhao Q., Wang C.S., Yang C. Enhanced activity of inositol-1,4,5-trisphosphate receptors in atrial myocytes of atrial fibrillation patients. Cardiology 2009; 114(3): 180–191. https://doi.org/10.1159/000228584
46. Hattori M., Suzuki A.Z., Higo T., Miyauchi H., Michikawa T., Nakamura T., Inoue T., Mikoshiba K. Distinct roles of inositol 1,4,5-trisphosphate receptor types 1 and 3 in Ca²⁺ signaling. J. Biol. Chem. 2004; 279(12): 11967–11975. https://doi.org/10.1074/jbc.m311456200
47. Belke D.D., Swanson E., Suarez J., Scott B.T., Stenbit A.E., Dillmann W.H. Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose. Am. J. Physiol. Heart Circ. Physiol. 2007; 292(4): H1755–H1763. https://doi.org/10.1152/ajpheart.00884.2006
48. Gambardella J., Trimarco B., Iaccarino G., Santulli G. New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling. Adv. Exp. Med. Biol. 2018; 1067: 373–385. https://doi.org/10.1007/5584_2017_106
49. Gonnot F., Boulogne L., Brun C., Dia M., Gouriou Y., Bidaux G., Chouabe C., Crola Da Silva C., Ducreux S., Pillot B., Kaczmarczyk A., Leon C., Chanon S., Perret C., Sciandra F., Dargar T., Gache V., Farhat F., Sebbag L., Bochaton T., Thibault H., Ovize M., Paillard M., Gomez L. SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases. Nat. Commun. 2023; 14(1): 3346. https://doi.org/10.1038/s41467-023-39027-x
50. Liu Y.B., Wang Q., Song Y.L., Song X.M., Fan Y.C., Kong L., Zhang J.S., Li S., Lv Y.J., Li Z.Y., Dai J.Y., Qiu Z.K. Abnormal phosphorylation / dephosphorylation and Ca²⁺ dysfunction in heart failure. Heart Fail. Rev. 2024; 29(4): 751–768. https://doi.org/10.1007/s10741-024-10395-w
51. Bencurova M., Lysikova T., Leskova Majdova K., Kaplan P., Racay P., Lehotsky J., Tatarkova Z. Age-Dependent Changes in Calcium Regulation after Myocardial Ischemia-Reperfusion Injury. Biomedicines 2023; 11(4): 1193. https://doi.org/10.3390/biomedicines11041193
52. Hamilton S., Terentyev D. Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart. Int. J. Mol. Sci. 2019; 20(10): 2386. https://doi.org/10.3390/ijms20102386
53. Del Monte F., Hajjar R.J. Intracellular devastation in heart failure. Heart Fail. Rev. 2008; 13(2): 151–162. https://doi.org/10.1007/s10741-007-9071-9
54. MacLennan D.H., Kranias E.G. Phospholamban: a crucial regulator of cardiac contractility. Nat. Rev. Mol. Cell Biol. 2003; 4(7): 566–577. https://doi.org/10.1038/nrm1151
55. Ragone I., Barallobre-Barreiro J., Takov K., Theofilatos K., Yin X., Schmidt L.E., Domenech N., Crespo-Leiro M.G., van der Voorn S.M., Vink A., van Veen T.A.B., Bödör C., Merkely B., Radovits T., Mayr M. SERCA2a Protein Levels Are Unaltered in Human Heart Failure. Circulation 2023; 148(7): 613–616. https://doi.org/10.1161/CIRCULATIONAHA.123.064513
Published
28-10-2025
How to Cite
Kozhevnikova L. M., Sukhanova I. F. Triggered Ca²⁺-dependent mechanism of early age-related impairments in cardiac contractile function in male and female rats // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 4. PP. 5–16.
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Original research
