Fluvastatin protects myocardial cells in mice with acute myocardial infarction through inhibiting RhoA/ROCK pathway

Yi,Zhenci; Ke,Jiaying; Wang,Yaoguo; Cai,Kaijin

doi:10.3892/etm.2020.8413

Fluvastatin protects myocardial cells in mice with acute myocardial infarction through inhibiting RhoA/ROCK pathway

Authors:
- Zhenci Yi
- Jiaying Ke
- Yaoguo Wang
- Kaijin Cai
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Affiliations: Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China, Department of Marine Biology, Quanzhou Normal University, Quanzhou, Fujian 362000, P.R. China, Department of Emergency, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
Published online on: January 3, 2020 https://doi.org/10.3892/etm.2020.8413
Pages: 2095-2102
Copyright: © Yi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Protective effect of fluvastatin (Flu) on myocardial cells in mice with acute myocardial infarction (AMI) and the mechanism were explored. Forty C57B/L6 mice in similar physiological status were selected and randomly divided into sham operation (Sham) group (n=10), AMI group (n=10), Flu group (n=10) and Flu + Angiotensin II (Ang II) (Ang II) group (n=10). The pathological changes in heart tissues were detected via hematoxylin and eosin (H&E) staining, and apoptosis of myocardial cells was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined using relevant kits, and the expression levels of Ras homolog gene family (Rho)-associated coiled-coil protein kinase 1 (ROCK1), ROCK2, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and nuclear factor-κB (NF-κB) in the infarction region were determined using Western blotting. The infarction area in mice in Flu group was significantly smaller than that in AMI group. In AMI group, the level of MDA in the serum and infarction tissues was remarkably higher than that in Sham group (P<0.05), while that of SOD significantly declined (P<0.05). The level of MDA in Flu group was obviously lower than that in AMI group (P<0.05). The expression levels of Bax, NF-κB, ROCK1 and ROCK2 were obviously higher in AMI group than those in Sham group, while they were obviously lower in Flu group than those in AMI group (P<0.05). After the Rho member A (RhoA)/ROCK pathway agonist Ang II was added, the mitigation effect of Flu on myocardial apoptosis in the infarction region in AMI mice was evidently weakened. Flu mitigates AMI-induced myocardial apoptosis in mice, and the possible mechanism is that the inflammatory and oxidative stress responses activated and mediated by RhoA/ROCK are effectively inhibited.

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1	Shiny KS, Kumar SH, Farvin KH, Anandan R and Devadasan K: Protective effect of taurine on myocardial antioxidant status in isoprenaline-induced myocardial infarction in rats. J Pharm Pharmacol. 57:1313–1317. 2005. View Article : Google Scholar : PubMed/NCBI
2	Carson DA and Ribeiro JM: Apoptosis and disease. Lancet. 341:1251–1254. 1993. View Article : Google Scholar : PubMed/NCBI
3	Wyllie AH, Kerr JF and Currie AR: Cell death: The significance of apoptosis. Int Rev Cytol. 68:251–306. 1980. View Article : Google Scholar : PubMed/NCBI
4	Yi J and An Y: Circulating miR-379 as a potential novel biomarker for diagnosis of acute myocardial infarction. Eur Rev Med Pharmacol Sci. 22:540–546. 2018.PubMed/NCBI
5	Baldi A, Abbate A, Bussani R, Patti G, Melfi R, Angelini A, Dobrina A, Rossiello R, Silvestri F, Baldi F, et al: Apoptosis and post-infarction left ventricular remodeling. J Mol Cell Cardiol. 34:165–174. 2002. View Article : Google Scholar : PubMed/NCBI
6	Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, et al: Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, −3, −6, −7, −8, and −10 in a caspase-9-dependent manner. J Cell Biol. 144:281–292. 1999. View Article : Google Scholar : PubMed/NCBI
7	Sam F, Sawyer DB, Chang DL, Eberli FR, Ngoy S, Jain M, Amin J, Apstein CS and Colucci WS: Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol. 279:H422–H428. 2000. View Article : Google Scholar : PubMed/NCBI
8	Wu J, Guo Z, Wang LL and Zhang RL: Degeneration of sensory afferent nerves enhances pulmonary inflammatory alterations in acute myocardial infarction in rats. Cardiovasc Pathol. 21:149–157. 2012. View Article : Google Scholar : PubMed/NCBI
9	Youle RJ and Strasser A: The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
10	Burridge K and Wennerberg K: Rho and Rac take center stage. Cell. 116:167–179. 2004. View Article : Google Scholar : PubMed/NCBI
11	Etienne-Manneville S and Hall A: Rho GTPases in cell biology. Nature. 420:629–635. 2002. View Article : Google Scholar : PubMed/NCBI
12	Shimokawa H: Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol. 39:319–327. 2002. View Article : Google Scholar : PubMed/NCBI
13	Yamakawa T, Tanaka S, Kamei J, Kadonosono K and Okuda K: Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2. J Atheroscler Thromb. 10:37–42. 2003. View Article : Google Scholar : PubMed/NCBI
14	Wiesbauer F, Kaun C, Zorn G, Maurer G, Huber K and Wojta J: HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: A comparative study using different statins. Br J Pharmacol. 135:284–292. 2002. View Article : Google Scholar : PubMed/NCBI
15	Kitano K, Usui S, Ootsuji H, Takashima S, Kobayashi D, Murai H, Furusho H, Nomura A, Kaneko S and Takamura M: Rho-kinase activation in leukocytes plays a pivotal role in myocardial ischemia/reperfusion injury. PLoS One. 9:e922422014. View Article : Google Scholar : PubMed/NCBI
16	Chang CC, Wang SS, Hsieh HG, Lee WS, Chuang CL, Lin HC, Lee FY, Lee SD and Huang HC: Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung. Clin Sci (Lond). 129:449–460. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Zhang H, Chai F, Liu X and Berk M: The effects of escitalopram on myocardial apoptosis and the expression of Bax and Bcl-2 during myocardial ischemia/reperfusion in a model of rats with depression. BMC Psychiatry. 14:3492014. View Article : Google Scholar : PubMed/NCBI
18	Chen TL, Zhu GL, He XL, Wang JA, Wang Y and Qi GA: Short-term pretreatment with atorvastatin attenuates left ventricular dysfunction, reduces infarct size and apoptosis in acute myocardial infarction rats. Int J Clin Exp Med. 7:4799–4808. 2014.PubMed/NCBI
19	Malick M, Gilbert K, Barry M, Godbout R and Rousseau G: Desvenlafaxine reduces apoptosis in amygdala after myocardial infarction. Brain Res Bull. 109:158–163. 2014. View Article : Google Scholar : PubMed/NCBI
20	Liu Q: Lentivirus mediated interference of Caspase-3 expression ameliorates the heart function on rats with acute myocardial infarction. Eur Rev Med Pharmacol Sci. 18:1852–1858. 2014.PubMed/NCBI
21	Kumphune S, Surinkaew S, Chattipakorn SC and Chattipakorn N: Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury. Pharm Biol. 53:1831–1841. 2015. View Article : Google Scholar : PubMed/NCBI
22	Motloch LJ, Hu J and Akar FG: The mitochondrial translocator protein and arrhythmogenesis in ischemic heart disease. Oxid Med Cell Longev. 2015:2341042015. View Article : Google Scholar : PubMed/NCBI
23	Zhang Q, Wang H, Yang YJ, Dong QT, Wang TJ, Qian HY, Li N, Wang XM and Jin C: Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: The role of the RhoA/ROCK/ERK pathway. Int J Cardiol. 176:670–679. 2014. View Article : Google Scholar : PubMed/NCBI
24	Loirand G, Guérin P and Pacaud P: Rho kinases in cardiovascular physiology and pathophysiology. Circ Res. 98:322–334. 2006. View Article : Google Scholar : PubMed/NCBI
25	Shi J and Wei L: Rho kinases in cardiovascular physiology and pathophysiology: The effect of fasudil. J Cardiovasc Pharmacol. 62:341–354. 2013. View Article : Google Scholar : PubMed/NCBI
26	Hung CN, Huang HP, Wang CJ, Liu KL and Lii CK: Sulforaphane inhibits TNF-α-induced adhesion molecule expression through the Rho A/ROCK/NF-κB signaling pathway. J Med Food. 17:1095–1102. 2014. View Article : Google Scholar : PubMed/NCBI
27	Bao W, Hu E, Tao L, Boyce R, Mirabile R, Thudium DT, Ma XL, Willette RN and Yue TL: Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury. Cardiovasc Res. 61:548–558. 2004. View Article : Google Scholar : PubMed/NCBI
28	Shimokawa H and Takeshita A: Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol. 25:1767–1775. 2005. View Article : Google Scholar : PubMed/NCBI
29	Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S and Takeshita A: Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: Effect on endothelial NAD(P)H oxidase system. Circ Res. 93:767–775. 2003. View Article : Google Scholar : PubMed/NCBI
30	Petrache I, Crow MT, Neuss M and Garcia JG: Central involvement of Rho family GTPases in TNF-alpha-mediated bovine pulmonary endothelial cell apoptosis. Biochem Biophys Res Commun. 306:244–249. 2003. View Article : Google Scholar : PubMed/NCBI
31	Del Re DP, Miyamoto S and Brown JH: RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. J Biol Chem. 282:8069–8078. 2007. View Article : Google Scholar : PubMed/NCBI
32	Chang J, Xie M, Shah VR, Schneider MD, Entman ML, Wei L and Schwartz RJ: Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. Proc Natl Acad Sci USA. 103:14495–14500. 2006. View Article : Google Scholar : PubMed/NCBI