Abstract
Aim:
The downregulation of phospholamban (PLB) and FKBP12.6 as a result of β-receptor activation is involved in the pathway(s) of congestive heart failure. We hypothesized that the endothelin (ET)-1 system may link to downregulated PLB and FKBP12.6.
Methods:
Rats were subjected to ischemia/reperfusion (I/R) to cause heart failure (HF). 1 mg/kg isoproterenol (ISO) was injected subcutaneously (sc) for 10 d to worsen HF. 30 mg/kg CPU0213 (sc), a dual ET receptor (ETAR/ETBR) antagonist was given from d 6 to d 10. On d 11, cardiac function was assessed together with the determination of mRNA levels of ryanodine receptor 2, calstabin-2 (FKBP12.6), PLB, and sarcoplasmic reticulum Ca2+-ATPase. Isolated adult rat ventricular myocytes were incubated with ISO at 1×10−6 mol/L to set up an in vitro model of HF. Propranolol (PRO), CPU0213, and darusentan (DAR, an ETAR antagonist) were incubated with cardiomyocytes at 1×10−5 mol/L or 1×10−6 mol/L in the presence of ISO (1×10−6 mol/L). Immunocytochemistry and Western blotting were applied for measuring the protein levels of PLB and FKBP12.6.
Results:
The worsened hemodynamics produced by I/R were exacerbated by ISO pretreatment. The significant downregulation of the gene expression of PLB and FKBP12.6 and worsened cardiac function by ISO were reversed by CPU0213. In vitro ISO 1×10−6 mol/L produced a sharp decline of PLB and FKBP12.6 proteins relative to the control. The downregulation of the protein expression was significantly reversed by the ET receptor antagonist CPU0213 or DAR, comparable to that achieved by PRO.
Conclusion:
This study demonstrates a role of ET in mediating the downregulation of the cardiac Ca2+-handling protein by ISO.
Similar content being viewed by others
Article PDF
References
Feldman DS, Carnes CA, Abraham WT, Bristow MR . Mechanisms of disease: beta-adrenergic receptors — alterations in signal transduction and pharmacogenomics in heart failure. Nat Clin Pract Cardiovasc Med 2005; 2: 475–83.
Schwinger RH . Treatment of heart failure with beta-receptor-blockers. Dtsch Med Wochenschr 2002; 127: 682–8.
Olson EN . A decade of discoveries in cardiac biology. Nat Med 2004; 10: 467–74.
Reiken S, Gaburjakova M, Guatimosim S, Gomez AM, D'Armiento J, Burkhoff D, et al. Protein kinase A phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts. Role of phosphatases and response to isoproterenol. J Biol Chem 2003; 278: 444–53.
Gupta RC, Mishra S, Rastogi S, Sharov VG, Sabbah HN . Improvement of cardiac sarcoplasmic reticulum calcium cycling in dogs with heart failure following long-term therapy with the Acorn Cardiac Support Device. Heart Fail Rev 2005; 10: 149–55.
Yano M, Ikeda Y, Matsuzaki M . Altered intracellular Ca2+ handling in heart failure. J Clin Invest 2005; 115: 556–64.
Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 2003; 299: 1410–3.
Temsah RM, Dyck C, Netticadan T, Chapman D, Elimban V, Dhalla NS . Effect of beta-adrenoceptor blockers on sarcoplasmic reticular function and gene expression in the ischemic-reperfused heart. J Pharmacol Exp Ther 2000; 293: 15–23.
Wehrens XH, Marks AR . Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Disc 2004; 3: 565–73.
Ertl G, Bauersachs J . Endothelin receptor antagonists in heart failure: current status and future directions. Drugs 2004; 64: 1029–40.
Teerlink JR, McMurray JJ, Bourge RC, Cleland JG, Cotter G, Jondeau G, et al. Tezosentan in patients with acute heart failure: design of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Study (VERITAS). Am Heart J 2005; 150: 46–53.
Anand I, McMurray J, Cohn JN, Konstam MA, Notter T, Quitzau K, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 347–54.
Kelland NF, Webb DJ . Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood) 2006; 231: 696–9.
Qi MY, Xia HJ, Dai DZ, Dai Y . A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a, and PLB in rats. J Cardiovasc Pharmacol 2006; 47: 729–35.
Dai DZ, Ji M, Huang M, Liu LG . Endothelin receptor antagonist activity and selective blocking the ETA and ETB of Compound 0213. J China Pharm Univ 2004; 35: 552–7.
Li L, Chu Y, Fink GD, Engelhardt JF, Heistad DD, Chen AF . Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension 2003; 42: 997–1003.
Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, et al. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004; 110: 1269–75.
Zhang TT, Cui B, Dai DZ . Downregulation of Kv4.2 and Kv4.3 channel gene expression in right ventricular hypertrophy induced by monocrotaline in rat. Acta Pharmacol Sin 2004; 25: 226–30.
Ma YP, Hu HJ, Hao XM, Zhou PA, Wu CH, Dai DZ . Reduced sodium currents in isolated mammalian myocytes treated with chronic L-thyroxine. Drug Dev Res 2003; 58: 111–5.
Weil J, Schunkert H . Pathophysiology of chronic heart failure. Clin Res Cardiol 2006; 95 ( Suppl 4): 1–17.
Armoundas AA, Rose J, Aggarwal R, Stuyvers BD, O'rourke B, Kass DA, et al. Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 2007; 292: H1607–18.
Sucharov CC . Beta-adrenergic pathways in human heart failure. Expert Rev Cardiovasc Ther 2007; 5: 119–24.
Armoundas AA, Rose J, Aggarwal R, Stuyvers B, O'Rourke B, Kass DA, et al. Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: Primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 2007; 292: H1607–18.
Saliaris AP, Amado LC, Minhas KM, Schuleri KH, Lehrke S, StJohn, M, et al. Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure. Am J Physiol Heart Circ Physiol 2007; 292: H1328–35.
Huang F, Shan J, Reiken S, Wehrens XH, Marks AR . Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice. Proc Natl Acad Sci USA 2006; 103: 3456–61.
Phrommintikul A, Chattipakorn N . Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. Int J Cardiol 2006; 112: 142–52.
Marin-Garcia J, Goldenthal MJ, Moe GW . Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure. J Card Fail 2002; 8: 326–32.
Xia HJ, Dai DZ, Dai Y . Up-regulated inflammatory factors endothelin, NFκB, TNF-α and iNOS involved in exaggerated cardiac arrhythmias in L-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats. Life Sci 2006; 79: 1812–9.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Natural Science Foundation of China (No 30670760).
Rights and permissions
About this article
Cite this article
Feng, Y., Tang, Xy., Dai, Dz. et al. Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin receptors. Acta Pharmacol Sin 28, 1746–1754 (2007). https://doi.org/10.1111/j.1745-7254.2007.00650.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2007.00650.x
Keywords
This article is cited by
-
Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress
Acta Pharmacologica Sinica (2016)
-
Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine
Journal of Biomedical Science (2012)
-
Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein
Acta Pharmacologica Sinica (2011)
-
CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity
Acta Pharmacologica Sinica (2010)
-
Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213
Acta Pharmacologica Sinica (2009)