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Dergiler / Journal of Experimental and Clinical Medicine / 2026 / Volume: 39 Issue: 2

Protective effects of tropisetron on diabetes-induced expression of genes involved in regulation of contractility, cardiomyopathy and apoptosis in the left ventricle of rats

Roya Naderi(urmia university of medical sciences)0000-0001-8529-7306
Alireza Shirpoor(urmia university of medical sciences)0000-0002-3663-6823
Mahrokh Samadi(urmia university of medical sciences)0000-0001-6493-1304
Farideh Nezamimajd(urmia university of medical sciences)0000-0003-2564-5991
Yousef Rasmi(urmia university of medical sciences)0000-0003-1506-1909
Morteza Bagheri(urmia university of medical sciences)0000-0002-4739-8517
Sayfa
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Yayın Tarihi
2022-03-18
DOI
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⚡ TL;DR(1 Cümlede Hızlı Çıkarım)

Collectively, our study provided strong evidence that 5-HT3 antagonist tropisetron was capable of attenuating the development of experimental diabetic cardiomyopathy associated with the reduction of intramyocardial MHCs and CaMKIIδ gene expression, inflammation and cardiac hypertrophy.

📌 3 Maddede Bu Makale

🎯
Amaç & Hipotez:Tropisetron, an antagonist of 5-HT3 receptor (5-HT3R), has exhibited a number of beneficial effects on the treatment of several diseases; however, its effect on diabetic cardiomyopathy, which is an important causal factor in morbidity and mortality among diabetic patients, remains to be fully elucidated.
📊
Temel Bulgular & Veri:After 14 days of treatment, the results revealed a significant increase in calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) total and isoforms δ2 and δ3 of CaMKIIδ, as well as myosin heavy chain (MHC)-β.
💡
Sonuç & Katkı:Collectively, our study provided strong evidence that 5-HT3 antagonist tropisetron was capable of attenuating the development of experimental diabetic cardiomyopathy associated with the reduction of intramyocardial MHCs and CaMKIIδ gene expression, inflammation and cardiac hypertrophy.
🔬Tür:Research Article
📍Kapsam:Genişletilmiş Akademik Örneklem
⚙️Değişkenler:Apoptosis · Diabetes · Tropisetron

Abstract

Tropisetron, an antagonist of 5-HT3 receptor (5-HT3R), has exhibited a number of beneficial effects on the treatment of several diseases; however, its effect on diabetic cardiomyopathy, which is an important causal factor in morbidity and mortality among diabetic patients, remains to be fully elucidated. Therefore, this study was designed to investigate the effect of tropisetron on diabetes-induced cardiomyopathy and the molecular mediators possibly involved. Twenty-four male wistar rats were assigned into three groups, control, diabetic, and tropisetron–treated diabetic groups. After 14 days of treatment, the results revealed a significant increase in calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) total and isoforms δ2 and δ3 of CaMKIIδ, as well as myosin heavy chain (MHC)-β. Furthermore, it decreased MHC-α gene expression among the diabetic group compared to the control group. Western blot analysis showed a significant increase in Bax and cleaved caspase 3 protein levels and a significant decrease in Bcl-2 contents in heart tissue of diabetic rats in comparison to the control rats. Moreover, the levels of Tumor necrosis factor alpha (TNF-α) , ICAM-1, and CaMKII in heart tissue of diabetic rats were significantly higher than those in the control rats. Significant amelioration of alteration in the genes expression and protein changes along with restoration of the elevated levels of TNF-α, ICAM-1, and CaMKII were found in the tropisetron–treated diabetic group compared to the diabetic group. Collectively, our study provided strong evidence that 5-HT3 antagonist tropisetron was capable of attenuating the development of experimental diabetic cardiomyopathy associated with the reduction of intramyocardial MHCs and CaMKIIδ gene expression, inflammation and cardiac hypertrophy.

🔖

Bu Makaleye Atıf Yap

Naderi, R., Shirpoor, A., Samadi, M., Nezamimajd, F., Rasmi, Y., Bagheri, M. (2022). Protective effects of tropisetron on diabetes-induced expression of genes involved in regulation of contractility, cardiomyopathy and apoptosis in the left ventricle of rats. Journal of Experimental and Clinical Medicine, Volume: 39 Issue: 2. https://ajindex.com/articles/1423045

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Kaynakça (83)

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  47. Becher, P M., Lindner, D., Frohlich, M., Savvatis, K., Westermann, D., Tschope, C. 2013. Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: a time course analysis. Int J Mol Med. 32: 158-164
  48. Cheng, S M., Ho, T J., Yang, A L., Chen, I J., Kao, C L., Wu, F N., Lin, J A., Kuo, C H., Ou, H C., Huang, C Y., Lee, S D. 2013. Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways in streptozotocin-induced diabetic rats. Int J Cardiol. 167: 478-485
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  54. Grimm, M., Ling, H., Willeford, A., Pereira, L., Gray, C B., Erickson, J R., Sarma, S., Respress, J L., Wehrens, X H., Bers, D M., Brown, J H. 2015. CaMKIIdelta mediates beta-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic beta-adrenergic stimulation. J Mol Cell Cardiol. 85: 282-291
  55. Heshmati, E., Shirpoor, A., Kheradmand, F., Alizadeh, M., Gharalari, F H. 2018. Chronic ethanol increases calcium/calmodulin-dependent protein kinaseIIdelta gene expression and decreases monoamine oxidase amount in rat heart muscles: Rescue effect of Zingiber officinale (ginger) extract. Anatol J Cardiol. 19: 19-26
  56. Hoch, B., Meyer, R., Hetzer, R., Krause, E G., Karczewski, P. 1999. Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ Res. 84: 713-721
  57. Hochhauser, E., Kivity, S., Offen, D., Maulik, N., Otani, H., Barhum, Y., Pannet, H., Shneyvays, V., Shainberg, A., Goldshtaub, V., Tobar, A., Vidne, B A. 2003. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am J Physiol Heart Circ Physiol. 284: H2351-2359
  58. Huo, R., Chen, C., Chen, Y., Li, Z., Hou, Y., Dong, D. 2012. 5-HT3 receptor antagonists protect against pressure overload-induced cardiac hypertrophy in murine. Acta Pharmaceutica Sinica B. 2: 16-22
  59. Izumo, S., Lompre, A M., Matsuoka, R., Koren, G., Schwartz, K., Nadal-Ginard, B., Mahdavi, V. 1987. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest. 79: 970-977
  60. Kayama, Y., Raaz, U., Jagger, A., Adam, M., Schellinger, I N., Sakamoto, M., Suzuki, H., Toyama, K., Spin, J M., Tsao, P S. 2015. Diabetic Cardiovascular Disease Induced by Oxidative Stress. Int J Mol Sci. 16: 25234-25263
  61. Kelly, R A., Smith, T W. 1997. Cytokines and cardiac contractile function. Circulation. 95: 778-781 20. Kroemer, G., Dallaporta, B., Resche-Rigon, M. 1998. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 60: 619-642
  62. Lee, T I., Kao, Y H., Chen, Y C., Huang, J H., Hsiao, F C., Chen, Y J. 2013. Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy. Diabetes Res Clin Pract. 100: 330-339
  63. Ling, H., Gray, C B., Zambon, A C., Grimm, M., Gu, Y., Dalton, N., Purcell, N H., Peterson, K., Brown, J H. 2013. Ca2+/Calmodulin-dependent protein kinase II delta mediates myocardial ischemia/reperfusion injury through nuclear factor-kappaB. Circ Res. 112: 935-944
  64. Longhurst, J C., Tjen, A L S C., Fu, L W. 2001. Cardiac sympathetic afferent activation provoked by myocardial ischemia and reperfusion. Mechanisms and reflexes. Ann N Y Acad Sci. 940: 74-95
  65. Luo, M., Guan, X., Luczak, E D., Lang, D., Kutschke, W., Gao, Z., Yang, J., Glynn, P., Sossalla, S., Swaminathan, P D., Weiss, R M., Yang, B., Rokita, A G., Maier, L S., Efimov, I R., Hund, T J., Anderson, M E. 2013. Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest. 123: 1262-1274
  66. Meehan, A G., Kreulen, D L. 1991. Electrophysiological studies on the interaction of 5-hydroxytryptamine with sympathetic transmission in the guinea pig inferior mesenteric artery and ganglion. J Pharmacol Exp Ther. 256: 82-87
  67. Mongeau, R., De Montigny, C., Blier, P. 1994. Activation of 5-HT3 receptors enhances the electrically evoked release of [3H]noradrenaline in rat brain limbic structures. Eur J Pharmacol. 256: 269-279
  68. Palmieri, V., Capaldo, B., Russo, C., Iaccarino, M., Pezzullo, S., Quintavalle, G., Di Minno, G., Riccardi, G., Celentano, A. 2008. Uncomplicated type 1 diabetes and preclinical left ventricular myocardial dysfunction: insights from echocardiography and exercise cardiac performance evaluation. Diabetes Res Clin Pract. 79: 262-268
  69. Rajesh, M., Mukhopadhyay, P., Batkai, S., Patel, V., Saito, K., Matsumoto, S., Kashiwaya, Y., Horvath, B., Mukhopadhyay, B., Becker, L., Hasko, G., Liaudet, L., Wink, D A., Veves, A., Mechoulam, R., Pacher, P. 2010. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 56: 2115-2125
  70. Shao, C H., Rozanski, G J., Nagai, R., Stockdale, F E., Patel, K P., Wang, M., Singh, J., Mayhan, W G., Bidasee, K R. 2010. Carbonylation of myosin heavy chains in rat heart during diabetes. Biochem Pharmacol. 80: 205-217
  71. Shao, C H., Rozanski, G J., Patel, K P., Bidasee, K R. 2007. Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats. J Mol Cell Cardiol. 42: 234-246
  72. Shirpoor, A., Heshmatian, B., Tofighi, A., Eliasabad, S N., Kheradmand, F., Zerehpoosh, M. 2019. Nandrolone administration with or without strenuous exercise increases cardiac fatal genes overexpression, calcium/calmodulin-dependent protein kinaseiidelta, and monoamine oxidase activities and enhances blood pressure in adult wistar rats. Gene. 697: 131-137
  73. Shirpoor, A., Ilkhanizadeh, B., Saadatian, R., Darvari, B S., Behtaj, F., Karimipour, M., Ghaderi-Pakdel, F., Saboori, E. 2006. Effect of vitamin E on diabetes-induced changes in small intestine and plasma antioxidant capacity in rat. J Physiol Biochem. 62: 171-177
  74. Shirpoor, A., Khadem Ansari, M H., Heshmatian, B., Ilkhanizadeh, B., Noruzi, L., Abdollahzadeh, N., Saboory, E. 2012. Decreased blood pressure with a corresponding decrease in adhesive molecules in diabetic rats caused by vitamin E administration. J Diabetes. 4: 362-368
  75. Shirpoor, A., Zerehpoosh, M., Ansari, M H K., Kheradmand, F., Rasmi, Y. 2017. Ginger extract mitigates ethanol-induced changes of alpha and beta – myosin heavy chain isoforms gene expression and oxidative stress in the heart of male wistar rats. DNA Repair. 57: 45-49
  76. Tak, P P., Firestein, G S. 2001. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 107: 7-11
  77. Wang, W., Ma, R. 2000. Cardiac sympathetic afferent reflexes in heart failure. Heart Fail Rev. 5: 57-71
  78. Wang, X T., Gong, Y., Zhou, B., Yang, J J., Cheng, Y., Zhao, J G., Qi, M Y. 2018. Ursolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats. Biomed Pharmacother. 97: 1461-1467
  79. Weiss, A., Leinwand, L A. 1996. The mammalian myosin heavy chain gene family. Annu Rev Cell Dev Biol. 12: 417-439
  80. Westermann, D., Van Linthout, S., Dhayat, S., Dhayat, N., Schmidt, A., Noutsias, M., Song, X Y., Spillmann, F., Riad, A., Schultheiss, H P., Tschope, C. 2007. Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 102: 500-507
  81. Wright, J W., Mizutani, S., Harding, J W. 2008. Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies. Heart Fail Rev. 13: 367-375
  82. Zhang, G X., Kimura, S., Nishiyama, A., Shokoji, T., Rahman, M., Yao, L., Nagai, Y., Fujisawa, Y., Miyatake, A., Abe, Y. 2005. Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res. 65: 230-238
  83. Zhang, T., Maier, L S., Dalton, N D., Miyamoto, S., Ross, J, Jr., Bers, D M., Brown, J H. 2003. The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res. 92: 912-919