SR 59230A on the expression of MicroRNAs in myocardium of heart failure rats

doi:10.12047/j.cjap.5561.2017.109

Abstract

Abstract: Objective: To investigate the effects of β3-adrenoceptors(β3-AR) inhibitor SR 59230A on MicroRNAs expression in rat myocardium with chronic heart failure and the related mechanisms.Methods: One hundred male SD rats were randomly divided into sham operated group(40)and chronic heart failure(CHF)group(60). Coronary artery ligation was used to induce CHF. Then the rats in CHF group were further randomly divided into CHF control group and CHF+SR 59230A group (CHF+SR). Rats in the sham group were divided into sham control group and sham+SR 59230A group (Sham+SR). The rats in Sham+SR group and CHF+SR group were treated with 1 ml SR 59230A(85 mmoL/L in 0.9% saline)twice a day for seven weeks by intraperitoneal injection, while the rats in control groups were injected with the same amount of saline for seven weeks separately. miScript miRNA PCR Arrays were used to determine the expression profile of MicroRNAs. Immunohistochemistry was used to evaluate the distribution of the related proteins in the heart tissue sections. Western blot was used to detect the expressions of nuclear factor-kappaB(NF-κB),p53 and p53-Phospho-Serine 15 in the heart.Results: ①After in vivo blockade of β3-AR by SR 59230A, there were 18MicroRNAs down-regulated in sham control group and CHF control group. Within them, 6 MicroRNAs were related to NF-κB signaling pathway, they were miR-125b-5p,miR-143-3p,miR-145-5p,miR-26a-5p,miR-30a-5p and miR-320-5p. ②Slides from the heart tissue showed that NF-κB was distributed both in nucleus and cytoplasm, while p53 in cytoplasm was more than that in nucleus in heart tissue sections. The expressions of NF-κB and p53 were higher in the CHF control group than those in the sham control group(P<0.05), but were lower in CHF+SR group than those in CHF control group(P<0.05),while they were elevated in Sham+SR group compared to the sham control group(P<0.05). ③ Compared with the sham control group, the protein expression of NF-κB p65 was increased significantly in the CHF control group (P<0.05). After treated with SR59230A in vivo,the protein expressions of NF-κB and p53-Phospho-Serine 15 were decreased significantly in CHF rats(P<0.05),while the protein expressions of NF-κB, p53 and p53-Phospho-Serine 15 proteins were increased in the sham rats (P<0.05).Conclusion: Blocking of β3-AR improved the damaged heart in CHF rats; β3-AR caused the change of MicroRNAs expression, and it related to NF-κB signal pathway.

Key words: rats, hearts, β3-adrenoceptors, SR 59230A, MicroRNAs, NF-κB

JING Jia-ni, LI Fan-lu, WANG Xi, WAN Xin, ZHAO Qian-qian, CUI Xiang-li. SR 59230A on the expression of MicroRNAs in myocardium of heart failure rats[J]. CJAP, 2017, 33(5): 456-460.

References

[1] Lange P. Chronic heart failure[J]. Aust Fam Physician, 2011, 40(6):362.
[2] Rengo G, Pagano G, Vitale DF, et al. Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure[J]. Eur J Nucl Med Mol Imaging, 2016, 43(13):2392-2400.
[3] Balligand JL. Beta3-adrenoreceptors in cardiovasular diseases:new roles for an "old" receptor[J]. Curr Drug Deliv, 2013, 10(1):64-66.
[4] Moniotte S, Kobzik L, Feron O, et al. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium[J]. Circulation, 2001, 103(12):1649-1655.
[5] 杨岚, 李海清, 李晓鹏, 等. β3肾上腺素能受体通过降低钙敏感性介导正常和心衰大鼠心脏的负性肌力作用[J]. 中国心血管病研究, 2015, 13(7):671-672.
[6] 赵倩倩, 景佳妮, 李海清, 等. β3-AR阻断剂SR 59230A对大鼠胸主动脉张力及microRNA表达的影响[J]. 中国应用生理学杂志, 2017, 33(1):6-10.
[7] Mamamtavrishvili ND, Kvirkveliia AA, Abashidze RI, et al. Role of immune inflammatory activity in chronic heart failure progress[J]. Georgian Med News, 2008(160-161):30-34.
[8] Gao E, Lei YH, Shang X, et al. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse[J]. Circ Res, 2010, 107(12):1445-1453.
[9] Gan RT, Li WM, Xiu CH, et al. Chronic blocking of beta 3-adrenoceptor ameliorates cardiac function in rat model of heart failure[J]. Chin Med J (Engl), 2007, 120(24):2250-2255.
[10] Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue[J]. Pathologe, 1987, 8(3):138-140.
[11] Rubattu S, Mennuni S, Testa M, et al. Pathogenesis of chronic cardiorenal syndrome:is there a role for oxidative stress[J]. Int J Mol Sci, 2013, 14(11):23011-23032.
[12] Maier HJ, Schips TG, Wietelmann A, et al. Cardiomyocyte-specific IkappaB kinase (IKK)/NF-kappaB activation induces reversible inflammatory cardiomyopathy and heart failure[J]. Proc Natl Acad Sci U S A, 2012, 109(29):11794-11799.
[13] Ryan KM, Ernst MK, Rice NR, et al. Role of NF-kappaB in p53-mediated programmed cell death[J]. Nature, 2000, 404(6780):892-897.
[14] De Rosa S, Curcio A, Indolfi C. Emerging role of microRNAs in cardiovascular diseases[J]. Circ J, 2014, 78(3):567-575.
[15] Dirkx E, Gladka MM, Philippen LE, et al. Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure[J]. Nat Cell Biol, 2013, 15(11):1282-1293.
[16] Sucharov C, Bristow MR, Port JD. miRNA expression in the failing human heart:functional correlates[J]. J Mol Cell Cardiol, 2008, 45(2):185-192.
[17] Eigsti RL, Sudan B, Wilson ME, et al. Regulation of activation-associated microRNA accumulation rates during monocyte-to-macrophage differentiation[J]. J Biol Chem, 2014, 289(41):28433-28447.
[18] Liu Q, Du GQ, Zhu ZT, et al. Identification of apoptosis-related microRNAs and their target genes in myocardial infarction post-transplantation with skeletal myoblasts[J]. J Transl Med, 2015, 13:270.
[19] Dong G, Fan H, Yang Y, et al. 17beta-Estradiol enhances the activation of IFN-alpha signaling in B cells by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p that target IKKepsilon. Biochim Biophys Acta, 2015, 1852(8):1585-1598.
[20] Rasheed Z, Al-Shobaili HA, Rasheed N, et al. MicroRNA-26a-5p regulates the expression of inducible nitric oxide synthase via activation of NF-kappaB pathway in human osteoarthritis chondrocytes[J]. Arch Biochem Biophys, 2016, 594:61-67.
[21] Marques FZ, Vizi D, Khammy O, et al. The transcardiac gradient of cardio-microRNAs in the failing heart[J]. Eur J Heart Fail, 2016, 18(8):1000-1008.