Abstract
Aim:
Dilated cardiomyopathy (DCM) is the most common cause of heart failure, and pharmacological intervention is not currently available. Here we investigate the effect of tetramethylpyrazine phosphate (TMPP) on the progression of DCM in the cTnTR141W transgenic mouse model.
Methods:
The cTnTR141W transgenic mice aged 2 months were divided into model group and TMPP group, whereas age-matched nontransgenic mice were used as wild-type control. TMPP 45 mg·kg−1·d−1 was administered for 7 months. Following assessment of cardiac function by echocardiography, cardiac tissues were prepared for histology and electron microscopy. Levels of molecular markers for cardiomyocyte hypertrophy and fibrosis were detected by RT-PCR. Expression of structural proteins of the sarcomere and intercalated disc was determined by Western blot.
Results:
TMPP significantly prevented cardiac dilatation and dysfunction with the development of DCM, and decreased mortality by 54%. TMPP decreased HW/BW ratios and expression of hypertrophic markers BNP and ACTA1, as well as reduced interstitial collagen deposition and expression of profibrotic markers Col1a1 and Col3a1. TMPP attenuated ultrastructural disruption caused by cTnTR141W expression and decreased expression of structural proteins myotilin and E-cadherin which were up-regulated in the cTnTR141W heart. Moreover, TMPP reduced the mRNA expression of Calm1 and Camk2b in the cTnTR141W heart.
Conclusion:
Our results suggest that TMPP could be a promising drug for prevention and treatment of DCM.
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References
Richardson P, Mckenna W, Bristow M, Maisch B, Mautner B, O'Connell J, et al. Report of the 1995 world health organization/international society and federation of cardiology task force on the definition and classification of cardiomyopathies. Circulation 1996; 93: 841–2.
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies. Circulation 2006; 113: 1807–16.
Jessup M, Brozena S . Heart failure. N Engl J Med 2003; 348: 2007–18.
Kamisago M, Sharma SD, Depalma SR, Solomon S, Sharma P, McDonough B, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343: 1688–96.
Towbin JA . The role of cytoskeletal proteins in cardiomyopathies. Curr Opin Cell Biol 1998; 10: 131–9.
Li D, Czernuszewicz GZ, Gonzalez O, Tapscott T, Karibe A, Durand JB, et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001; 104: 2188–93.
Juan F, Wei D, Xiongzhi Q, Ran D, Chunmei M, Lan H, et al. The changes of the cardiac structure and function in cTnTR141W transgenic mice. Int J Cardiol 2008; 128: 83–90.
Kwan CY, Daniel CE, Chen MC . Inhibition of vasoconstriction by tetramethylpyrazine: Does it act by blocking the voltage-dependent Ca2+ channel? J Cardiovasc Pharmacol 1990; 15: 157–62.
Sheu JR, Kan YC, Hung WC, Lin CH, Yen MH . The antiplatelet activity of tetramethylpyrazine is mediated through activation of NO synthase. Life Sci 2000; 67: 937–47.
Zhang Z, Wei T, Hou J, Li G, Yu S, Xin W . Tetramethylpyrazine scavenges superoxide anion and decreases nitric oxide production in human polymorphonuclear leukocytes. Life Sci 2003; 72: 2465–72.
Pang PK, Shan JJ, Chiu KW . Tetramethylpyrazine, a calcium antagonist. Planta Med 1996; 62: 431–5.
Hintz KK, Ren J . Tetramethylpyrazine elicits disparate responses in cardiac contraction and intracellular Ca2+ transients in isolated adult rat ventricular myocytes. Vasc Pharmacol 2003; 40: 213–7.
Chen KJ, Chen K . Ischemic stroke treated with Ligusticum chuanxiong. Chin Med J 1992; 105: 870–3.
Sutter MC, Wang YX . Recent cardiovascular drugs from Chinese medicinal plants. Cardiovasc Res 1993; 27: 1891–901.
Aoki J, Ikari Y, Nakajima H, Mori M, Sugimoto T, Hatori M, et al. Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients. Kidney International 2005; 67: 333–40.
Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, et al. The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol 1995; 27: 291–305.
Kajstura J, Zhang X, Liu Y, Szoke E, Cheng W, Olivetti G, et al. The cellular basis of pacing-induced dilated cardiomyopathy. Circulation 1995; 92: 2306–17.
Branishte TA, Dudnakova TV, Dergilev KV, Severin VV, Naumov VG, Shirinski VP, et al. Expression of contractile and cytoskeletal proteins in myocardium of patients with dilated cardiomyopathy. Kardiologiia 2004; 44: 31–6.
Arber S, Hunter JJ, Ross J Jr, Hongo M, Sansig G, Borg J, et al. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 1997; 88: 393–403.
Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol 2004; 44: 2192–201.
Duboscq-Bidot L, Xu P, Charron P, Neyroud N, Dilanian G, Millaire A, et al. Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc Res 2008; 77: 118–25.
Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, et al. Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 2005; 96: 346–54.
Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, et al. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet 2003; 12: 189–203.
Zeller R, Ivandic BT, Ehlermann P, Mucke O, Zugck C, Remppis A, et al. Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE. J Mol Med 2006; 84: 682–91.
Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 2000; 9: 2141–7.
Hauser MA, Conde CB, Kowaljow V, Zeppa G, Taratuto AL, Torian UM, et al. Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet 2002; 71: 1428–82.
Garvey SM, Liu Y, Miller SE, Hauser MA . Myotilin overexpression enhances myopathology in the LGMD1A mouse model. Muscle Nerve 2008; 37: 663–7.
Moza M, Mologni L, Trokovic R, Faulkner G, Partanen J, Carpén O . Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice. Mol Cell Biol 2007; 27: 244–52.
Perriard JC, Hirschy A, Ehler E . Dilated cardiomyopathy: a disease of the intercalated disc? Trends Cardiovasc Med 2003; 13: 30–8.
Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, et al. Alterations at the intercalated disk associated with the absence of muscle LIM protein. J Cell Biol 2001; 153: 763–72.
Ferreira-Cornwell MC, Luo Y, Narula N, Lenox JM, Lieberman M, Radice GL . Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart. J Cell Sci 2002; 115: 1623–34.
Zhang T, Brown JH . Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. Cardiovasc Res 2004; 63: 476–86.
Maier LS, Zhang T, Chen L, DeSantiago J, Brown JH, Bers DM . Transgenic CaMKIIδC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ Res 2003; 92: 904–11.
Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 2005; 11: 409–17.
Acknowledgements
The authors thank Dr Harold JAMES for his patiently reading and correcting the English writing of this paper. The present work was supported in part by the National Commonwealth Institute Foundation (No DWS200704) and the Ministry of Health (No 200802036).
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Zhao, Hp., Lü, D., Zhang, W. et al. Protective action of tetramethylpyrazine phosphate against dilated cardiomyopathy in cTnTR141W transgenic mice. Acta Pharmacol Sin 31, 281–288 (2010). https://doi.org/10.1038/aps.2010.6
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DOI: https://doi.org/10.1038/aps.2010.6
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