Cardiovascular Pharmacology

Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017

Abstract

Aim:

The occurrence of ventricular fibrillation (VF) is dependent on the deterioration of channelopathy in the myocardium. It is interesting to investigate molecular changes in relation to abrupt appearance of VF on reperfusion. We aimed to study whether changes in the expression of FKBP12.6 and SERCA2a and the endothelin (ET) system on reperfusion against ischemia were related to the rapid occurrence of VF and whether CPU86017, a class III antiarrhythmic agent which blocks IKr, IKs, and ICa.L, suppressed VF by correcting the molecular changes on reperfusion.

Methods:

Cardiomyopathy (CM) was produced by 0.4 mg/kg sc L-thyroxin for 10 d in rats, and subjected to 10 min coronary artery ligation/reperfusion on d 11. Expressions of the Ca2+ handling and ET system and calcium transients were conducted and CPU86017 was injected (4 mg/kg, sc) on d 6–10.

Results:

A high incidence of VF was found on reperfusion of the rat CM hearts, but there was no VF before reperfusion. The elevation of diastolic calcium was significant in the CM myocytes and exhibited abnormality of the Ca2+ handling system. The rapid downregulation of mRNA and the protein expression of FKBP12.6 and SERCA2a were found on reperfusion in association with the upregulation of the expression of the endothelin-converting enzyme (ECE) and protein kinase A (PKA), in contrast, no change in the ryanodine type 2 receptor (RyR2), phospholamban (PLB), endothelin A receptor (ETAR), and iNOS was found. CPU86017 removed these changes and suppressed VF.

Conclusion:

Abrupt changes in the expression of FKBP12.6, SERCA2a, PKA, and ECE on reperfusion against ischemia, which are responsible for the rapid occurrence of VF, have been observed. These changes are effectively prevented by CPU86017.

References

  1. 1

    Roberts R, Brugada R . Genetics and arrhythmias. Annu Rev Med, 2003; 54: 257–67.

    CAS  Article  Google Scholar 

  2. 2

    Dai DZ, Yu F . Ion channelopathy and hyperphosphorylation contributing to cardiac arrhythmias. Acta Pharmacol Sin, 2005; 26: 918–25.

    CAS  Article  Google Scholar 

  3. 3

    Rubart M, Zipes DP . Mechanisms of sudden cardiac death. J Clin Invest, 2005; 115: 2305–15.

    CAS  Article  Google Scholar 

  4. 4

    Sen-Chowdhry S, McKenna WJ . Sudden cardiac death in the young: a strategy for prevention by targeted evaluation. Cardiology, 2006; 105: 196–206.

    Article  Google Scholar 

  5. 5

    Schwartz PJ . Management of long QT syndrome. Nat Clin Pract Cardiovasc Med, 2005; 2: 346–51.

    Article  Google Scholar 

  6. 6

    Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ . Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases. Mayo Clin Proc, 2004; 79: 1380–4.

    CAS  Article  Google Scholar 

  7. 7

    Olson EN . A decade of discoveries in cardiac biology. Nat Med, 2004; 10: 467–74.

    CAS  Article  Google Scholar 

  8. 8

    Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 2003; 113: 829–40.

    CAS  Article  Google Scholar 

  9. 9

    Dai DZ . Two patterns of ion channelopathy in the myocardium: perspectives for development of anti-arrhythmic agents. Curr Opin Investig Drugs, 2005; 6: 289–97.

    CAS  PubMed  Google Scholar 

  10. 10

    Yu F, Dai DZ, An LF, Guo XF . Heart hypertrophy induced by levothyroxine aggravates ischemic lesions and reperfusion arrhythmias in rats. Acta Pharmacol Sin, 1997; 18: 71–4.

    CAS  Google Scholar 

  11. 11

    Dai DZ, Hu HJ, Yang DM, Hao XM, Zhang GQ, Zhou PA, et al. Chronic levothyroxin treatment is associated with ion channel abnormalities in cardiac and neuronal cells. Clin Exp Pharmacol Physiol, 1999; 26: 819–21.

    CAS  Article  Google Scholar 

  12. 12

    Wang HL, Li SB, Dai DZ . Change on L-type calcium current in single guinea pig hypertrophic ventricular myocytes induced by levothyroxine. J China Pharm Univ, 2000; 31: 130–4.

    CAS  Google Scholar 

  13. 13

    Zhang GQ, Hao XM, Ma YP, Zhou PA, Wu CH, Dai DZ . Characteristics of the delayed rectifier K+ current in guinea pig hypertrophied ventricular myocytes induced by thyroxin. China Pharmacol Bull, 2001; 17: 174–7.

    Google Scholar 

  14. 14

    Zhang GQ, Ma YP, Hao XM, Zhou PA, Wu CH, Dai DZ . Rapidly activating delayed rectifier K+ current and inward rectifier K+ current in cardiomyocytes from hypertrophied guinea pig hearts induced by thyroxine. J China Pharm Univ, 2000; 31: 451–4.

    CAS  Google Scholar 

  15. 15

    Brugada R, Hong K, Cordeiro JM, Dumaine R . Short QT syndrome. CMAJ, 2005; 173: 1349–54.

    Article  Google Scholar 

  16. 16

    Xia HJ, Dai DZ, Dai Y . Up-regulated inflammatory factors endothelin, NF?B, TNF-α and iNOS involved in exaggerated cardiac arrhythmias in L-thyroxin induced cardiomyopathy are suppressed by darusentan in rats. Life Sci, 2006; 79: 1812–9.

    CAS  Article  Google Scholar 

  17. 17

    Dai DZ . CPU86017: a novel class III antiarrhythmic agent with multiple actions at ion channels. Cardiovasc Drug Rev, 2006; 24: 100–14.

    Article  Google Scholar 

  18. 18

    Kao JP, Harootunian AT, Tsien RY . Photochemically generated cytosolic calcium pulses and their detection by Fluo-3. J Biol Chem, 1989; 264: 8179–84.

    CAS  PubMed  Google Scholar 

  19. 19

    Virag L, Scott GS, Antal-Szalmas P, O'Connor M, Ohshima H, Szabo C . Requirement of intracellular calcium mobilization for peroxynitrite-induced poly(ADP-ribose) synthetase activation and cytotoxicity. Mol Pharmacol, 1999; 56: 824–33.

    CAS  PubMed  Google Scholar 

  20. 20

    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.

    CAS  Article  Google Scholar 

  21. 21

    Katra RP, Laurita KR . Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res, 2005; 96: 535–42.

    CAS  Article  Google Scholar 

  22. 22

    Wehrens XH, Marks AR . Sudden unexplained death caused by cardiac ryanodine receptor (RyR2) mutations. Mayo Clin Proc, 2004; 79: 1367–71.

    Article  Google Scholar 

  23. 23

    Wu XD, Dai DZ, Zhang QP, Gao F . Propranolol and verapamil inhibit mRNA expression of RyR2 and SERCA in L-thyroxin-induced rat ventricular hypertrophy. Acta Pharmacol Sin, 2004; 25: 347–51.

    CAS  PubMed  Google Scholar 

  24. 24

    Wang YQ, Shi YP, Dai DZ . Therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats. Drug Dev Res, 2004; 63: 22–32.

    CAS  Article  Google Scholar 

  25. 25

    Ligeti L, Szenczi O, Prestia CM, Szabo C, Horvath K, Marcsek ZL, et al. Altered calcium handling is an early sign of streptozotocin-induced diabetic cardiomyopathy. Int J Mol Med, 2006; 17: 1035–43.

    CAS  PubMed  Google Scholar 

  26. 26

    Gambliel HA, Burke BE, Cusack BJ, Walsh GM, Zhang YL, Mushlin PS, et al. Doxorubicin and C-13 deoxydoxorubicin effects on ryanodine receptor gene expression. Biochem Biophys Res Commun, 2002; 291: 433–8.

    CAS  Article  Google Scholar 

  27. 27

    Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, et al. FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Biochem Biophys Res Commun, 2001; 281: 979–86.

    CAS  Article  Google Scholar 

  28. 28

    Miyauchi T, Masaki T . Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol, 1999; 61: 391–415.

    CAS  Article  Google Scholar 

  29. 29

    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.

    CAS  Article  Google Scholar 

  30. 30

    Temsah RM, Netticadan T, Chapman D, Takeda S, Mochizuki S, Dhalla NS . Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am J Physiol, 1999; 277: H584–94.

    CAS  PubMed  Google Scholar 

  31. 31

    Gupta SK, Saxena A, Singh U, Arya DS . Bosentan, the mixed ETA-ETB endothelin receptor antagonist, attenuated oxidative stress after experimental myocardial ischemia and reperfusion. Mol Cell Biochem, 2005; 275: 67–74.

    CAS  Article  Google Scholar 

  32. 32

    Hao JM, Dai DZ, Yu F . The oxidative stress enhancing effects by L-thyroxin and the antioxidant effects of CPU 86017, a derivative of tetrahydroberberine. Prog Pharmaceut Sci, 2005; 29: 417–21.

    CAS  Google Scholar 

  33. 33

    Nakaya H, Furusawa Y, Ogura T, Tamagawa M, Uemura H . Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. Br J Pharmacol, 2000; 131: 1363–72.

    CAS  Article  Google Scholar 

  34. 34

    Kohno M, Yano M, Kobayashi S, Doi M, Oda T, Tokuhisa T, et al. A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. Am J Physiol Heart Circ Physiol, 2003; 284: H1035–42.

    CAS  Article  Google Scholar 

  35. 35

    Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart, 2003; 89: 66–70.

    CAS  Article  Google Scholar 

  36. 36

    Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M . Short QT syndrome. Cardiovasc Res, 2005; 67: 357–66.

    CAS  Article  Google Scholar 

  37. 37

    Piccirillo G, Magri D, Matera S, Magnanti M, Torrini A, Pasquazzi E, et al. QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study. Eur Heart J 2006 Nov 13; [Epub ahead of print].

  38. 38

    Thomsen MB, Verduyn SC, Stengl M, Beekman JD, de Pater G, van Opstal J, et al. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation, 2004; 110: 2453–9.

    Article  Google Scholar 

  39. 39

    Tomaselli GF, Zipes D P . What causes sudden death in heart failure? Circ Res 2004; 95: 754–63.

    CAS  Article  Google Scholar 

  40. 40

    Gollob MH . Genetic profiling as a marker for risk of sudden cardiac death. Curr Opin Cardiol, 2006; 21: 42–6.

    Article  Google Scholar 

  41. 41

    Chow BJ, Gollob M, Birnie D . Brugada syndrome precipitated by a tricyclic antidepressant. Heart, 2005; 91: 651.

    CAS  Article  Google Scholar 

  42. 42

    Woo SH, Lee CO . Effects of endothelin-1 on Ca2+ signaling in guinea-pig ventricular myocytes: role of protein kinase C. J Mol Cell Cardiol, 1999; 31: 631–43.

    CAS  Article  Google Scholar 

  43. 43

    Chen J, Mehta JL . Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone. Am J Physiol Heart Circ Physiol, 2006; 291: H1738–45.

    CAS  Article  Google Scholar 

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Correspondence to De-zai Dai.

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Project supported by the National Natural Science Foundation of China (No 30572193 and 30230170).

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Na, T., Huang, Zj., Dai, Dz. et al. Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017. Acta Pharmacol Sin 28, 773–782 (2007). https://doi.org/10.1111/j.1745-7254.2007.00580.x

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Keywords

  • sudden cardiac death
  • ventricular fibrillation endothelin
  • FKBP12.6
  • SERCA2a
  • protein kinase A
  • CPU86017
  • cardiomyopathy
  • L-thyroxin
  • endothelin-converting enzyme

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