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Effect of ouabain on myocardial ultrastructure and cytoskeleton during the development of ventricular hypertrophy

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Abstract

The aim of this work is to study cytoskeletal impairment during the development of ouabain-induced ventricular hypertrophy. Male Sprague–Dawley rats were treated with either ouabain or saline. Systolic blood pressure (SBP) was recorded weekly. At the end of the 3rd and 6th week, the rats were killed and cardiac mass index were measured. Hematoxylin–eosin and Sirius red staining were carried out and cardiac ultrastructure were studied using transmission electron microscopy. The mRNA level of Profilin-1, Desmin, PCNA, TGF-β1 and ET-1 in the left ventricle were measured using real-time quantitative PCR while their protein levels were examined by Western blot or immunohistochemistry. After 3 weeks, there was no significant difference in the mean SBP, cardiac mass index, mRNA and protein expression of PCNA, TGF-β1 and ET-1 between the two groups. However, ouabain-treated rats showed disorganized cardiac cytoskeleton with abnormal expression of Profilin-1 and Desmin. After 6 weeks, the cardiac mass index remained the same in the two groups while PCNA, TGF-β1, and ET-1 have been upregulated in ouabain-treated rats. The cardiac cytoskeletal impairment was more severe in ouabain-treated rats with further changes of Profilin-1 and Desmin. Cytoskeletal abnormality is an ultra-early change during ouabain-induced ventricular hypertrophy, before the release of hypertrophic factors. Therapy for prevention of ouabain-induced hypertrophy should start at the early stage by preventing the cytoskeleton from disorganization.

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References

  1. Xie Z, Cai T (2003) Na+-K+-ATPase-mediated signal transduction: from protein interaction to cellular function. Mol Interv 3:157–168

    Article  PubMed  CAS  Google Scholar 

  2. Schoner W, Scheiner-Bobis G (2007) Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs 7:173–189

    Article  PubMed  CAS  Google Scholar 

  3. Manunta P, Ferrandi M, Bianchi G, Hamlyn JM (2009) Endogenous ouabain in cardiovascular function and disease. J Hypertens 27:9–18

    Article  PubMed  CAS  Google Scholar 

  4. Ferrandi M, Molinari I, Barassi P, Minotti E, Bianchi G, Ferrari P (2004) Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238. J Biol Chem 279:33306–33314

    Article  PubMed  CAS  Google Scholar 

  5. Kometiani P, Li J, Gnudi L, Kahn BB, Askari A, Xie Z (1998) Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. J Biol Chem 273:15249–15256

    Article  PubMed  CAS  Google Scholar 

  6. Huang L, Li H, Xie Z (1997) Ouabain-induced hypertrophy in cultured cardiac myocytes is accompanied by changes in expression of several late response genes. J Mol Cell Cardiol 29:429–437

    Article  PubMed  CAS  Google Scholar 

  7. Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z (2000) Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 275:27838–27844

    PubMed  CAS  Google Scholar 

  8. Collins JF, Pawloski-Dahm C, Davis MG, Ball N, Dorn GW 2nd, Walsh RA (1996) The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J Mol Cell Cardiol 28:1435–1443

    Article  PubMed  CAS  Google Scholar 

  9. Qiu J, Gao HQ, Zhou RH, Liang Y, Zhang XH, Wang XP, You BA, Cheng M (2007) Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull 30:247–253

    Article  PubMed  CAS  Google Scholar 

  10. Moustafa-Bayoumi M, Alhaj MA, El-Sayed O, Wisel S, Chotani MA, Abouelnaga ZA, Hassona MD, Rigatto K, Morris M, Nuovo G, Zweier JL, Goldschmidt-Clermont P, Hassanain H (2007) Vascular hypertrophy and hypertension caused by transgenic overexpression of profilin 1. J Biol Chem 282:37632–37639

    Article  PubMed  CAS  Google Scholar 

  11. Kim HR, Graceffa P, Ferron F, Gallant C, Boczkowska M, Dominguez R, Morgan KG (2010) Actin polymerization in differentiated vascular smooth muscle cells requires vasodilator-stimulated phosphoprotein. Am J Physiol Cell Physiol 298:C559–C571

    Article  PubMed  CAS  Google Scholar 

  12. Costa ML, Escaleira R, Cataldo A, Oliveira F, Mermelstein CS (2004) Desmin: molecular interactions and putative functions of the muscle intermediate filament protein. Braz J Med Biol Res 37:1819–1830

    Article  PubMed  CAS  Google Scholar 

  13. Tolstonog GV, Sabasch M, Traub P (2002) Cytoplasmic intermediate filaments are stably associated with nuclear matrices and potentially modulate their DNA-binding function. DNA Cell Biol 21:213–239

    Article  PubMed  CAS  Google Scholar 

  14. Monreal G, Nicholson LM, Han B, Joshi MS, Phillips AB, Wold LE, Bauer JA, Gerhardt MA (2008) Cytoskeletal remodeling of desmin is a more accurate measure of cardiac dysfunction than fibrosis or myocyte hypertrophy. Life Sci 83:786–794

    Article  PubMed  CAS  Google Scholar 

  15. Yuan CM, Manunta P, Hamlyn JM, Chen S, Bohen E, Yeun J, Haddy FJ, Pamnani MB (1993) Long-term ouabain administration produces hypertension in rats. Hypertension 22:178–187

    Article  PubMed  CAS  Google Scholar 

  16. Tian G, Dang C, Lu Z (2001) The change and significance of the Na+-K+-ATPase alpha-subunit in ouabain-hypertensive rats. Hypertens Res 24:729–734

    Article  PubMed  CAS  Google Scholar 

  17. Hamlyn JM, Manunta P (1992) Ouabain, digitalis-like factors and hypertension. J Hypertens Suppl 10:S99–S111

    Article  PubMed  CAS  Google Scholar 

  18. Lewis LK, Yandle TG, Lewis JG, Richards AM, Pidgeon GB, Kaaja RJ, Nicholls MG (1994) Ouabain is not detectable in human plasma. Hypertension 24:549–555

    Article  PubMed  CAS  Google Scholar 

  19. Gruson D, Ginion A, Decroly N, Lause P, Vanoverschelde JL, Ketelslegers JM, Bertrand L, Thissen JP (2011) Urocortin-induced cardiomyocytes hypertrophy is associated with regulation of the GSK-3beta pathway. Heart Vessels. doi:10.1007/s00380-011-0141-5

  20. Kamal FA, Watanabe K, Ma M, Abe Y, Elbarbary R, Kodama M, Aizawa Y (2011) A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy. Heart Vessels 26:81–90

    Article  PubMed  Google Scholar 

  21. Manunta P, Stella P, Rivera R, Ciurlino D, Cusi D, Ferrandi M, Hamlyn JM, Bianchi G (1999) Left ventricular mass, stroke volume, and ouabain-like factor in essential hypertension. Hypertension 34:450–456

    Article  PubMed  CAS  Google Scholar 

  22. Jiang X, Ren YP, Lv ZR (2007) Ouabain induces cardiac remodeling in rats independent of blood pressure. Acta Pharmacol Sin 28:344–352

    Article  PubMed  CAS  Google Scholar 

  23. Manunta P, Rogowski AC, Hamilton BP, Hamlyn JM (1994) Ouabain-induced hypertension in the rat: relationships among plasma and tissue ouabain and blood pressure. J Hypertens 12:549–560

    Article  PubMed  CAS  Google Scholar 

  24. Capetanaki Y (2000) Desmin cytoskeleton in healthy and failing heart. Heart Fail Rev 5:203–220

    Article  PubMed  CAS  Google Scholar 

  25. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL (2001) Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33:1065–1089

    Article  PubMed  CAS  Google Scholar 

  26. Liu T, Brown DA, O’Rourke B (2010) Role of mitochondrial dysfunction in cardiac glycoside toxicity. J Mol Cell Cardiol 49:728–736

    Article  PubMed  CAS  Google Scholar 

  27. Yarmola EG, Bubb MR (2006) Profilin: emerging concepts and lingering misconceptions. Trends Biochem Sci 31:197–205

    Article  PubMed  CAS  Google Scholar 

  28. Machesky LM, Poland TD (1993) Profilin as a potential mediator of membrane-cytoskeleton communication. Trends Cell Biol 3:381–385

    Article  PubMed  CAS  Google Scholar 

  29. Romeo GR, Kazlauskas A (2008) Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1. J Biol Chem 283:9595–9605

    Article  PubMed  CAS  Google Scholar 

  30. Si J, Collins SJ (2008) Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Res 68:3733–3742

    Article  PubMed  CAS  Google Scholar 

  31. Onishi A, Chen Q, Humtsoe JO, Kramer RH (2008) STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells. Exp Cell Res 314:377–386

    Article  PubMed  CAS  Google Scholar 

  32. Takekoshi K, Ishii K, Kawakami Y, Isobe K, Nanmoku T, Nakai T (2001) Ca(2+) mobilization, tyrosine hydroxylase activity, and signaling mechanisms in cultured porcine adrenal medullary chromaffin cells: effects of leptin. Endocrinology 142:290–298

    Article  PubMed  CAS  Google Scholar 

  33. Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, Devaux B, Bauer E, Klovekorn WP, Schlepper M, Schaper W, Schaper J (2000) Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ Res 86:846–853

    Article  PubMed  CAS  Google Scholar 

  34. Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 134:1255–1270

    Article  PubMed  CAS  Google Scholar 

  35. Chen F, Chang R, Trivedi M, Capetanaki Y, Cryns VL (2003) Caspase proteolysis of desmin produces a dominant-negative inhibitor of intermediate filaments and promotes apoptosis. J Biol Chem 278:6848–6853

    Article  PubMed  CAS  Google Scholar 

  36. Milner DJ, Taffet GE, Wang X, Pham T, Tamura T, Hartley C, Gerdes AM, Capetanaki Y (1999) The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function. J Mol Cell Cardiol 31:2063–2076

    Article  PubMed  CAS  Google Scholar 

  37. El-Ani D, Stav H, Guetta V, Arad M, Shainberg A (2011) Rapamycin (sirolimus) protects against hypoxic damage in primary heart cultures via Na+/Ca2+ exchanger activation. Life Sci 89:7–14

    Article  PubMed  CAS  Google Scholar 

  38. Maruyama R, Takemura G, Tohse N, Ohkusa T, Ikeda Y, Tsuchiya K, Minatoguchi S, Matsuzaki M, Fujiwara T, Fujiwara H (2006) Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes. Am J Physiol Heart Circ Physiol 290:H1493–H1502

    Article  PubMed  CAS  Google Scholar 

  39. Weisleder N, Soumaka E, Abbasi S, Taegtmeyer H, Capetanaki Y (2004) Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement. J Mol Cell Cardiol 36:121–128

    Article  PubMed  CAS  Google Scholar 

  40. Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000) Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 150:1283–1298

    Article  PubMed  CAS  Google Scholar 

  41. Capetanaki Y (2002) Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. Trends Cardiovasc Med 12:339–348

    Article  PubMed  CAS  Google Scholar 

  42. (1997) Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. N Engl J Med 336:309–315

Download references

Acknowledgments

This study was supported by grants from the National Nature Science Foundation of China (30700884), Shandong Science and Technology Research Plan (2010GGC10294) and Shandong Outstanding Young and Middle-aged Scientists Research Award Fund (BS2009SW015) to Dr. Jie Qiu. The authors of this manuscript have certified that they comply with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals [42].

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Authors and Affiliations

  1. Department of Geriatric Cardiology, Qilu Hospital of Shandong University, 107 Wenhua Xi Rd, 250012, Jinan, People’s Republic of China

    Shao-hua Zhao, Hai-qing Gao, Xiang Ji, Yan Wang, Xiang-ju Liu, Bei-an You, Xiao-pei Cui & Jie Qiu

  2. Shandong Provincial Key laboratory of Cardiovascular Proteomics, 107 Wenhua Xi Rd, 250012, Jinan, People’s Republic of China

    Shao-hua Zhao, Hai-qing Gao, Xiang Ji, Yan Wang & Jie Qiu

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  1. Shao-hua Zhao
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Correspondence to Jie Qiu.

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Zhao, Sh., Gao, Hq., Ji, X. et al. Effect of ouabain on myocardial ultrastructure and cytoskeleton during the development of ventricular hypertrophy. Heart Vessels 28, 101–113 (2013). https://doi.org/10.1007/s00380-011-0219-0

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  • DOI: https://doi.org/10.1007/s00380-011-0219-0

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