The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models

Gao,Hai-Cheng; Zhao,Hang; Zhang,Wen-Qi; Li,Yun-Qian; Ren,Li-Qun

doi:10.3892/etm.2013.935

The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models

Authors:
- Hai-Cheng Gao
- Hang Zhao
- Wen-Qi Zhang
- Yun-Qian Li
- Li-Qun Ren
View Affiliations

Affiliations: Department of Clinical Pharmacy and Pharmaceutical Management, Jilin University, Changchun 130021, P.R. China, Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, P.R. China, Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
Published online on: January 30, 2013 https://doi.org/10.3892/etm.2013.935
Pages: 1123-1128

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

The aim of this study was to investigate the role of the Rho/Rho associated coiled coil-forming protein kinase (Rock) signaling pathway in the pathogenesis of ischemic myocardial fibrosis (MF) in rats. The MF rat model was established using isoprenaline hydrochloride (ISO, 15 mg/kg). Rats were randomly divided into ten groups: a control group and ISO-treated groups at 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 7 days and 21 days . The MF model was evaluated by serum enzyme levels, hematoxylin and eosin (H&E) staining and Masson's staining, ex vivo. The mRNA expression of RhoA and Rock I was assessed with reverse transcription-polymerase chain reaction (RT-PCR). The cell type was evaluated by immunofluorescent and immunohistochemical staining. The protein expression of Rock I was evaluated using western blotting and immunohistochemistry. MF was found to be more developed in the ISO-treated group compared with the control group. CD31 and vimentin expression in fibroblasts and endothelial cells were significantly increased. In addition, the mRNA and protein levels of RhoA and Rock I were significantly increased. In conclusion, activation of Rho/Rock accelerates the degree of ischemic MF. Inhibition of Rho/Rock may be a novel therapeutic strategy for the prevention of ischemic MF.

View Figures

View References

1	Porter KE and Turner NA: Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 123:255–278. 2009. View Article : Google Scholar : PubMed/NCBI
2	Díez J: Mechanisms of cardiac fibrosis in hypertension. J Clin Hypertens (Greenwich). 9:546–550. 2007.
3	Dreesen O and Brivanlou AH: Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev. 3:7–17. 2007. View Article : Google Scholar : PubMed/NCBI
4	Bove PF and van der Vliet A: Nitric oxide and reactive nitrogen species in airway epithelial signaling and inflammation. Free Radic Biol Med. 41:515–527. 2006. View Article : Google Scholar : PubMed/NCBI
5	Tapia PC: RhoA, Rho kinase, JAK2 and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1 and leptin may all conspire to promote stem cell exhaustion. Med Hypotheses. 66:570–576. 2006. View Article : Google Scholar : PubMed/NCBI
6	Burch ML, Zheng W and Little PJ: Smad linker region phosphorylation in the regulation of extracellular matrix synthesis. Cell Mol Life Sci. 68:97–107. 2011. View Article : Google Scholar : PubMed/NCBI
7	Hudson VM: Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic Biol Med. 30:1440–1461. 2001. View Article : Google Scholar : PubMed/NCBI
8	Murata I, Takenaka K, Yoshinoya S, Kikuchi K, Kiuchi T, Tanigawa T and Ito K: Clinical evaluation of pulmonary and hypertension in systemic scleros related disorders: A Doppler echocardiographic study of 135 Japanese patients. Chest. 111:36–43. 1997. View Article : Google Scholar : PubMed/NCBI
9	Tian B and Kaufman PL: Effects of the Rho kinase inhibitor Y-27632 and the phosphatase inhibitor Calyculin A on outflow facility in monkeys. Exp Eye Res. 80:215–225. 2005. View Article : Google Scholar : PubMed/NCBI
10	Nagatoya K, Moriyama T, Kawada N, Takeji M, Oseto S, Murozono T, Ando A, Imai E and Hori M: Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 61:1684–1695. 2002. View Article : Google Scholar : PubMed/NCBI
11	Gao X, He X, Luo B, Peng L, Lin J and Zuo Z: Angiotensin II increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts. Eur J Pharmacol. 606:115–120. 2009. View Article : Google Scholar : PubMed/NCBI
12	Stange EF, Travis SP, Vermeire S, Beglinger C, et al: European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. Gut. 55(Suppl 1): i1–i15. 2006.
13	Kell DB: Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics. 2:1–79. 2009.PubMed/NCBI
14	Velders M, Schleipen B, Fritzemeier KH, Zierau O and Diel P: Selective estrogen receptor-β activation stimulates skeletal muscle growth and regeneration. FASEB J. 26:1909–1920. 2012.
15	Cheng XW, Shi GP, Kuzuya M, Sasaki T, Okumura K and Murohara T: Role for cysteine protease cathepsins in heart disease focus on biology and mechanisms with clinical implication. Circulation. 125:1551–1562. 2012. View Article : Google Scholar : PubMed/NCBI
16	Strieter RM, Keeley EC, Burdick MD and Mehrad B: The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Trans Am Clin Climatol Assoc. 120:49–59. 2009.PubMed/NCBI
17	Kolavennu V, Zeng L, Peng H, Wang Y and Danesh FR: Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes. 57:714–723. 2008. View Article : Google Scholar : PubMed/NCBI
18	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
19	Zhou H, Li YJ, Wang M, Zhang LH, Guo BY, Zhao ZS, Meng FL, Deng YG and Wang RY: Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes. Acta Pharmacol Sin. 32:999–1008. 2011. View Article : Google Scholar : PubMed/NCBI