Tetramethylpyrazine inhibits angiotensin II-induced cardiomyocyte hypertrophy and tumor necrosis factor-α secretion through an NF-κB-dependent mechanism

Yu,Liangzhu; She,Tonghui; Li,Mincai; Shi,Chunrong; Han,Lu; Cheng,Menglin

doi:10.3892/ijmm.2013.1436

Tetramethylpyrazine inhibits angiotensin II-induced cardiomyocyte hypertrophy and tumor necrosis factor-α secretion through an NF-κB-dependent mechanism

Authors:
- Liangzhu Yu
- Tonghui She
- Mincai Li
- Chunrong Shi
- Lu Han
- Menglin Cheng
View Affiliations

Affiliations: School of Basic Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China, Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
Published online on: July 9, 2013 https://doi.org/10.3892/ijmm.2013.1436
Pages: 717-722

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tetramethylpyrazine (TMP), a bioactive compound isolated from the Chinese herb, Ligusticum wallichii Franchat, has been reported to play a protective role in cardiac diseases. However, the cellular and molecular mechanisms behind the protective effects of TMP on the heart remain to be elucidated. In this study, we aimed to determine the effects of TMP on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and its possible mechanisms of action. In addition, we investigated whether TMP regulates tumor necrosis factor-α (TNF-α) secretion and expression. We found that TMP significantly inhibited the Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by the decrease in [3H]leucine incorporation and β-myosin heavy chain (β‑MHC) mRNA expression. TMP inhibited Ang II-stimulated TNF-α protein secretion and mRNA expression in the cardiomyocytes. Further experiments revealed that Ang II increased the level of the phosphorylated form of the transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), as well as NF-κB-DNA binding activity in the cardiomyocytes; treatment with TMP significantly inhibited the Ang II-induced activation of NF-κB. Furthermore, the inhibition of NF-κB by the specific inhibitor, pyrrolidine dithiocarbamate (PDTC), markedly attenuated the Ang II-induced increase in [3H]leucine incorporation, β-MHC mRNA expression and TNF-α protein secretion. Our findings suggest that TMP inhibits Ang II-induced cardiomyocyte hypertrophy and TNF-α production through the suppression of the NF-κB pathway, which may provide new insight into the mechanisms underlying the protective effects of TMP in heart diseases.

View Figures

View References

1	Levy D, Garrison RJ, Savage DD, Kannel WB and Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 322:1561–1566. 1990. View Article : Google Scholar : PubMed/NCBI
2	Sadoshima J and Izumo S: Molecular characterization of angiotensin II - induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 73:413–423. 1993. View Article : Google Scholar : PubMed/NCBI
3	Lee KH, Jang Y and Chung JH: Heat shock protein 90 regulates IkappaB kinase complex and NF-kappaB activation in angiotensin II-induced cardiac cell hypertrophy. Exp Mol Med. 42:703–711. 2010. View Article : Google Scholar : PubMed/NCBI
4	Gupta S, Young D, Maitra RK, et al: Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol. 375:637–649. 2008. View Article : Google Scholar : PubMed/NCBI
5	Chen KJ and Chen K: Ischemic stroke treated with Ligusticum chuanxiong. Chin Med J (Engl). 105:870–873. 1992.
6	Sutter MC and Wang YX: Recent cardiovascular drugs from Chinese medicinal plants. Cardiovasc Res. 27:1891–1901. 1993. View Article : Google Scholar : PubMed/NCBI
7	Feng J, Wu G and Tang S: The effects of tetramethylpyrazine on the incidence of arrhythmias and the release of PGI2 and TXA2 in the ischemic rat heart. Planta Med. 65:268–270. 1999. View Article : Google Scholar : PubMed/NCBI
8	Fan L, Wang K, Shi Z, Die J, Wang C and Dang X: Tetramethylpyrazine protects spinal cord and reduces inflammation in a rat model of spinal cord ischemia-reperfusion injury. J Vasc Surg. 54:192–200. 2011. View Article : Google Scholar : PubMed/NCBI
9	Liu CF, Lin CH, Chen CF, Huang TC and Lin SC: Antioxidative effects of tetramethylpyrazine on acute ethanol-induced lipid peroxidation. Am J Chin Med. 33:981–988. 2005. View Article : Google Scholar : PubMed/NCBI
10	Wang GJ, Wang HX, Yao YS, Guo LY and Liu P: The role of Ca²⁺/calmodulin-dependent protein kinase II and calcineurin in TNF-alpha-induced myocardial hypertrophy. Braz J Med Biol Res. 45:1045–1051. 2012.
11	Hu Y, Li T, Wang Y, et al: Tollip attenuated the hypertrophic response of cardiomyocytes induced by IL-1beta. Front Biosci. 14:2747–2756. 2009. View Article : Google Scholar : PubMed/NCBI
12	Yokoyama T, Sekiguchi K, Tanaka T, et al: Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts. Am J Physiol. 276:H1968–H1976. 1999.PubMed/NCBI
13	Huang Y, Zhang H, Shao Z, et al: Suppression of endothelin-1-induced cardiac myocyte hypertrophy by PPAR agonists: role of diacylglycerol kinase zeta. Cardiovasc Res. 90:267–275. 2011. View Article : Google Scholar : PubMed/NCBI
14	Feng J, Liu R, Wu G and Tang S: Effects of tetramethylpyrazine on the release of PGI2 and TXA2 in the hypoxic isolated rat heart. Mol Cell Biochem. 167:153–158. 1997. View Article : Google Scholar : PubMed/NCBI
15	Zou LY, Hao XM, Zhang GQ, Zhang M, Guo JH and Liu TF: Effect of tetramethyl pyrazine on L-type calcium channel in rat ventricular myocytes. Can J Physiol Pharmacol. 79:621–626. 2001. View Article : Google Scholar : PubMed/NCBI
16	Gao S, Chen ZW, Zheng H and Chen XL: Ligustrazine attenuates acute myocardium injury after thermal trauma. Burns. 33:321–327. 2007. View Article : Google Scholar : PubMed/NCBI
17	Zhao HP, Lu D, Zhang W, et al: Protective action of tetramethylpyrazine phosphate against dilated cardiomyopathy in cTnT(R141W) transgenic mice. Acta Pharmacol Sin. 31:281–288. 2010. View Article : Google Scholar : PubMed/NCBI
18	Rajapurohitam V, Kilic A, Javadov S and Karmazyn M: Role of NF-kappaB and p38 MAPK activation in mediating angiotensin II and endothelin-1-induced stimulation in leptin production and cardiomyocyte hypertrophy. Mol Cell Biochem. 366:287–297. 2012. View Article : Google Scholar : PubMed/NCBI
19	Liu Q, Chen Y, Auger-Messier M and Molkentin JD: Interaction between NFkappaB and NFAT coordinates cardiac hypertrophy and pathological remodeling. Circ Res. 110:1077–1086. 2012. View Article : Google Scholar : PubMed/NCBI
20	Valente AJ, Clark RA, Siddesha JM, Siebenlist U and Chandrasekar B: CIKS (Act1 or TRAF3IP2) mediates angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy. J Mol Cell Cardiol. 53:113–124. 2012. View Article : Google Scholar : PubMed/NCBI
21	Freund C, Schmidt-Ullrich R, Baurand A, et al: Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation. 111:2319–2325. 2005. View Article : Google Scholar : PubMed/NCBI
22	Wang D and Baldwin AS Jr: Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J Biol Chem. 273:29411–29416. 1998. View Article : Google Scholar : PubMed/NCBI
23	Baldwin AS Jr: The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 14:649–683. 1996. View Article : Google Scholar : PubMed/NCBI
24	Kawano S, Kubota T, Monden Y, et al: Blockade of NF-kappaB ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II. Cardiovasc Res. 67:689–698. 2005. View Article : Google Scholar : PubMed/NCBI
25	Sun M, Chen M, Dawood F, et al: Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation. 115:1398–1407. 2007. View Article : Google Scholar : PubMed/NCBI
26	Janczewski AM, Kadokami T, Lemster B, Frye CS, McTiernan CF and Feldman AM: Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha. Am J Physiol Heart Circ Physiol. 284:H960–H969. 2003. View Article : Google Scholar : PubMed/NCBI
27	Nakamura K, Fushimi K, Kouchi H, et al: Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation. 98:794–799. 1998. View Article : Google Scholar : PubMed/NCBI
28	Ock S, Ahn J, Lee SH, et al: Receptor activator of nuclear factor-kappaB ligand is a novel inducer of myocardial inflammation. Cardiovasc Res. 94:105–114. 2012. View Article : Google Scholar : PubMed/NCBI
29	Sriramula S, Haque M, Majid DS and Francis J: Involvement of tumor necrosis factor-alpha in angiotensin II-mediated effects on salt appetite, hypertension, and cardiac hypertrophy. Hypertension. 51:1345–1351. 2008. View Article : Google Scholar : PubMed/NCBI