Changes in cAMP signaling are associated with age-related downregulation of spontaneously beating atrial tissue energetic indices

GeroScience - Tập 45 - Trang 209-219 - 2022
Noa Kirschner Peretz1, Sofia Segal1, Rotem Shapira1, Ori Shemla1, Yevgeniya Lukyanenko2, Inbar Brosh1, Edward G. Lakatta3, Kenta Tsutsui3,4, Yael Yaniv1
1Faculty of Biomedical Engineering, Technion-IIT, Haifa, Israel
2Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, USA
3Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, USA
4Department of Cardiovascular Medicine, Saitama Medical University International Medical Center, Saitama, Japan

Tóm tắt

The prevalence of atria-related diseases increases exponentially with age and is associated with ATP supply-to-demand imbalances. Because evidence suggests that cAMP regulates ATP supply-to-demand, we explored aged-associated alterations in atrial ATP supply-to-demand balance and its correlation with cAMP levels. Right atrial tissues driven by spontaneous sinoatrial node impulses were isolated from aged (22–26 months) and adult (3–4 months) C57/BL6 mice. ATP demand increased by addition of isoproterenol or 3-Isobutyl-1-methylxanthine (IBMX) and decreased by application of carbachol. Each drug was administrated at the dose that led to a maximal change in beating rate (Xmax) and to 50% of that maximal change in adult tissue (X50). cAMP, NADH, NAD + NADH, and ATP levels were measured in the same tissue. The tight correlation between cAMP levels and the beating rate (i.e., the ATP demand) demonstrated in adult atria was altered in aged atria. cAMP levels were lower in aged compared to adult atrial tissue exposed to X50 of ISO or IBMX, but this difference narrowed at Xmax. Neither ATP nor NADH levels correlated with ATP demand in either adult or aged atria. Baseline NADH levels were lower in aged as compared to adult atria, but were restored by drug perturbations that increased cAMP levels. Reduction in Ca2+-activated adenylyl cyclase-induced decreased cAMP and prolongation of the spontaneous beat interval of adult atrial tissue to their baseline levels in aged tissue, brought energetics indices to baseline levels in aged tissue. Thus, cAMP regulates right atrial ATP supply-to-demand matching and can restore age-associated ATP supply-to-demand imbalance.

Tài liệu tham khảo

Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation. Circ Res. Lippincott Williams & WilkinsHagerstown, MD; 2014;114:1453–68.

Roberts-Thomson K, Kistler P, Sanders P, Morton J, Haqqani H, Stevenson I, et al. Fractionated atrial electrograms during sinus rhythm: relationship to age, voltage, and conduction velocity. Hear Rhythm Heart Rhythm. 2009;6:587–91.

Allessie M, Boyden P, Camm A, Kléber A, Lab M, Legato M, et al. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001;103:769–77.

Emelyanova L, Preston C, Gupta A, Viqar M, Negmadjanov U, Edwards S, et al. Effect of aging on mitochondrial energetics in the human atria. J Gerontol A Biol Sci Med Sci. J Gerontol A Biol Sci Med Sci 2018;73:608–16.

Nemutlu E, Gupta A, Zhang S, Viqar M, Holmuhamedov E, Terzic A, Jahangir A, Dzeja P. Decline of phosphotransfer and substrate supply metabolic circuits hinders ATP cycling in aging myocardium. PLoS ONE. 2015;10:e0136556.

Emelyanova L, Ashary Z, Cosic M, Negmadjanov U, Ross G, Rizvi F, et al. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol. 2016;311:H54-63.

Yaniv Y, Juhaszova M, Nuss HBB, Wang S, Zorov DBB, Lakatta EGG, et al. Matching ATP supply and demand in mammalian heart in vivo, in vitro, and in silico perspectives. Anal Card Dev From Embryo Old Age. 2010;1188:133–42.

Yaniv Y, Juhaszova M, Sollott SJJ. Age-related changes of myocardial ATP supply and demand mechanisms. Trends Endocrinol Metab. 2013;24:495–505.

Yan J, Zhao W, Thomson JK, Gao X, DeMarco DM, Carrillo E, et al. Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis. Circ Res Lippincott Williams and Wilkins. 2018;122:821–35.

Xu W, Li L, Zhang L. NAD+ metabolism as an emerging therapeutic target for cardiovascular diseases associated with sudden cardiac death. Front Physiol. Frontiers Media SA; 2020;11.

Nattel S. Aging and protein kinase activation. Circ Res. Lippincott Williams & WilkinsHagerstown, MD; 2018;122:799–801.

Niemann B, Pan R, Teschner M, Boening A, Silber R, Rohrbach S. Age and obesity-associated changes in the expression and activation of components of the AMPK signaling pathway in human right atrial tissue. Exp Gerontol Exp Gerontol. 2013;48:55–63.

Liu J, Sirenko S, Juhaszova M, Sollott SJ, Shukla S, Yaniv Y, et al. Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling. Am J Physiol Hear Circ Physiol. 2014;306:H1385–97.

Behar JA, Rosenberg AA, Weiser-Bitoun I, Shemla O, Alexandrovich A, Konyukhov E, et al. PhysioZoo: a novel open access platform for heart rate variability analysis of mammalian electrocardiographic data. Front Physiol. 2018;9:1390.

Shemla O, Tsutsui K, Behar JA, Yaniv Y. Beating rate variability of isolated mammal sinoatrial node tissue: insight into its contribution to heart rate variability. Front Neurosci. Frontiers Media SA; 2021;14.

Yaniv Y, Ahmet I, Tsutsui K, Behar J, Moen JM, Okamoto Y, et al. Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo. Aging Cell. 2016;15.

Collins TP, Terrar DA. Ca(2+)-stimulated adenylyl cyclases regulate the L-type Ca(2+) current in guinea-pig atrial myocytes. J Physiol. 2012;590:1881–93.

Tellez JO, Mączewski M, Yanni J, Sutyagin P, Mackiewicz U, Atkinson A, et al. Ageing-dependent remodelling of ion channel and Ca 2+ clock genes underlying sino-atrial node pacemaking. Exp Physiol. 2011;96:1163–78.

Chang H, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25:138–45.

Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056–60.

Mougenot N, Mika D, Czibik G, Marcos E, Abid S, Houssaini A, et al. Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction. Cardiovasc Res. 2019;115:1778–90.

Katz LA, Koretsky AP, Balaban RS. Respiratory control in the glucose perfused heart: A 31P NMR and NADH fluorescence study. FEBS Lett. No longer published by Elsevier; 1987;221:270–6.

Moreno-Sánchez R, Hogue BA, Hansford RG. Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation. Biochem J. Portland Press Ltd; 1990;268:421.

Zhou L, Cabrera ME, Okere IC, Sharma N, Stanley WC. Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies. Am J Physiol-Heart Circ Physiol. 2006;291:H1036–46.

Covian R, Balaban RS. Cardiac mitochondrial matrix and respiratory complex protein phosphorylation. Am J Physiol-Heart Circ Physiol. 2012;303:H940–66.

Bera AK, Ghosh S, Das S. Mitochondrial VDAC can be phosphorylated by cyclic AMP-dependent protein kinase. Biochem Biophys Res Commun. Academic Press; 1995;209:213–7.

Sheldon KL, Maldonado EN, Lemasters JJ, Rostovtseva TK, Bezrukov SM. Phosphorylation of voltage-dependent anion channel by serine/threonine kinases governs its interaction with tubulin. PLoS ONE. 2011;6:e25539.

Herraiz-Martínez A, Álvarez-García J, Llach A, Molina C, Fernandes J, Ferrero-Gregori A, et al. Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. Cardiovasc Res. 2015;106:76–86.

Balaban RS. The role of Ca2+ signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim Biophys Acta - Bioenerg. 2009;1787:1334–41.

Glancy B, Hartnell LM, Malide D, Yu Z-X, Combs CA, Connelly PS, et al. Mitochondrial reticulum for cellular energy distribution in muscle. Nature. 2015;523:617–20.

Barton GP, de Lange WJ, Ralphe JC, Aiken J, Diffee G. Linking metabolic and contractile dysfunction in aged cardiac myocytes. Physiological Reports. 2017;5:e13485.

Preston CC, Oberlin AS, Holmuhamedov EL, Gupta A, Sagar S, Syed RHK, et al. Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart. Mech Ageing Dev Elsevier. 2008;129:304–12.

Kalifa J, Maixent J-M, Chalvidan T, Dalmasso C, Colin D, Cozma D, et al. Energetic metabolism during acute stretch-related atrial fibrillation. Mol Cell Biochem. 2008;317:69–75.

Dobrev D, Voigt N, Wehrens XHT. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res. 2011;89.

Dobrev D, Nattel S. Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J Cardiovasc Pharmacol. 2008;52:293–9.

Vest JA, Wehrens XHT, Reiken SR, Lehnart SE, Dobrev D, Chandra P, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation Circulation. 2005;111:2025–32.

El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, et al. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation. 2006;114:670–80.

Greiser M, Neuberger HR, Harks E, El-Armouche A, Boknik P, de Haan S, et al. Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation. J Mol Cell Cardiol. 2009;46:385–94.

Thông tin
Thông tin xuất bản

GeroScience

Tập 45

209-219

Thông tin tác giả