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Cardiovascular Toxicology
Published in: Cardiovascular Toxicology 4/2020

01-08-2020 | Myocardial Infarction

Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism

Authors: Refaat A. Eid, Samah A. Alharbi, Attalla Farag El-kott, Samy M. Eleawa, Mohamed Samir Ahmed Zaki, Fahmy El-Sayed, Muhammad Alaa Eldeen, Hussain Aldera, Abd Al-Rahman Salem Al-Shudiefat

Published in: Cardiovascular Toxicology | Issue 4/2020

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Abstract

Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.
Literature
1.
Suthahar, N., Meijers, W. C., Silljé, H. H., & de Boer, R. A. (2017). From inflammation to fibrosis—Molecular and cellular mechanisms of myocardial tissue remodelling and perspectives on differential treatment opportunities. Current Heart Failure Reports,14, 235–250.PubMedPubMedCentralCrossRef
2.
Schirone, L., Forte, M., Palmerio, S., Yee, D., Nocella, C., Angelini, F., et al. (2017). A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxidative Medicine and Cellular Longevity,2017, 3920195.PubMedPubMedCentralCrossRef
3.
Hill, J. A., & Olson, E. N. (2008). Cardiac plasticity. New England Journal of Medicine,358, 1370–1380.CrossRef
4.
Ohtani, T., Mohammed, S. F., Yamamoto, K., Dunlay, S. M., Weston, S. A., Sakata, Y., et al. (2012). Diastolic stiffness as assessed by diastolic wall strain is associated with adverse remodelling and poor outcomes in heart failure with preserved ejection fraction. European Heart Journal,33, 1742–1749.PubMedPubMedCentralCrossRef
5.
6.
Pacher, P., Liaudet, L., Bai, P., Virag, L., Mabley, J., Hasko, G., et al. (2002). Activation of poly (ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. Journal of Pharmacology and Experimental Therapeutics,300, 862–867.CrossRef
7.
Szabo, C. (2005). Pharmacological inhibition of poly (ADP-ribose) polymerase in cardiovascular disorders: Future directions. Current Vascular Pharmacology,3, 301–303.PubMedCrossRef
8.
Wang, J., Hao, L., Wang, Y., Qin, W., Wang, X., Zhao, T., et al. (2015). Inhibition of poly (ADP-ribose) polymerase and inducible nitric oxide synthase protects against ischemic myocardial damage by reduction of apoptosis. Molecular Medicine Reports,11, 1768–1776.PubMedCrossRef
9.
Sun, S., Hu, Y., Zheng, Q., Guo, Z., Sun, D., Chen, S., et al. (2019). Poly (ADP-ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity. Journal of Cellular Biochemistry,120, 4813–4826.PubMedCrossRef
10.
Ling, X. X., Liu, J. X., Lin, Y., Du, Y. J., Chen, S. Q., Chen, J. L., et al. (2016). Poly(ADP-ribosyl)ation of apoptosis antagonizing transcription factor involved in hydroquinone-induced DNA damage response. Biomedical and Environmental Sciences,29, 80–84.PubMed
11.
d’Amours, D., Desnoyers, S., d’Silva, I., & Poirier, G. G. (1999). Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochemical Journal,342, 249.PubMedCentralCrossRef
12.
Rajamohan, S. B., Pillai, V. B., Gupta, M., Sundaresan, N. R., Birukov, K. G., Samant, S., et al. (2009). SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly (ADP-ribose) polymerase 1. Molecular and Cellular Biology,29, 4116–4129.PubMedPubMedCentralCrossRef
13.
Szabo, C., Zingarelli, B., O'Connor, M., & Salzman, A. L. (1996). DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proceedings of the National Academy of Sciences,93, 1753–1758.CrossRef
14.
Hassa, P., & Hottiger, M. (2002). The functional role of poly (ADP-ribose) polymerase 1 as novel coactivator of NF-κB in inflammatory disorders. Cellular and Molecular Life Sciences,59, 1534–1553.PubMedCrossRef
15.
Yao, L., Huang, K., Huang, D., Wang, J., Guo, H., & Liao, Y. (2008). Acute myocardial infarction induced increases in plasma tumor necrosis factor-α and interleukin-10 are associated with the activation of poly (ADP-ribose) polymerase of circulating mononuclear cell. International Journal of Cardiology,123, 366–368.PubMedCrossRef
16.
Halmosi, R., Deres, L., Gal, R., Eros, K., Sumegi, B., & Toth, K. (2016). PARP inhibition and postinfarction myocardial remodeling. International Journal of Cardiology,217, S52–S59.PubMedCrossRef
17.
Jia, G., Zao, M., & Liu, X. (2017). Protective effect of diethylcarbamazine inhibits NF-κB activation in isoproterenol-induced acute myocardial infarction rat model through the PARP pathway. Molecular Medicine Reports,16, 1596–1602.PubMedCrossRef
18.
Hans, C. P., Zerfaoui, M., Naura, A. S., Catling, A., & Boulares, A. H. (2008). Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability. Cardiovascular Research,78, 429–439.PubMedCrossRef
19.
Eid, R. A., Zaki, M. S. A., Al-Shraim, M., Eleawa, S. M., El-kott, A. F., Al-Hashem, F. H., et al. (2018). Subacute ghrelin administration inhibits apoptosis and improves ultrastructural abnormalities in remote myocardium post-myocardial infarction. Biomedicine & Pharmacotherapy,101, 920–928.CrossRef
20.
Drucker, D. J. (2016). The cardiovascular biology of glucagon-like peptide-1. Cell Metabolism,24, 15–30.PubMedCrossRef
21.
Timmers, L., Henriques, J. P., de Kleijn, D. P., DeVries, J. H., Kemperman, H., Steendijk, P., et al. (2009). Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. Journal of the American College of Cardiology,53, 501–510.PubMedCrossRef
22.
Woo, J. S., Kim, W., Ha, S. J., Kim, J. B., Kim, S.-J., Kim, W.-S., et al. (2013). Cardioprotective effects of exenatide in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention: Results of exenatide myocardial protection in revascularization study. Arteriosclerosis, Thrombosis, and Vascular Biology,33, 2252–2260.PubMedCrossRef
23.
Noyan-Ashraf, M. H., Shikatani, E. A., Schuiki, I., Mukovozov, I., Wu, J., Li, R.-K., et al. (2013). A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation,127, 74–85.PubMedCrossRef
24.
Aravindhan, K., Bao, W., Harpel, M. R., Willette, R. N., Lepore, J. J., & Jucker, B. M. (2015). Cardioprotection resulting from glucagon-like peptide-1 administration involves shifting metabolic substrate utilization to increase energy efficiency in the rat heart. PLoS ONE,10, e0130894.PubMedPubMedCentralCrossRef
25.
Li, J., Zheng, J., Wang, S., Lau, H. K., Fathi, A., & Wang, Q. (2017). Cardiovascular benefits of native GLP-1 and its metabolites: An indicator for GLP-1-therapy strategies. Frontiers in Physiology,8, 15.PubMedPubMedCentral
26.
Robinson, E., Cassidy, R. S., Tate, M., Zhao, Y., Lockhart, S., Calderwood, D., et al. (2015). Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Research in Cardiology,110, 20.PubMedPubMedCentralCrossRef
27.
Tate, M., Robinson, E., Green, B. D., McDermott, B. J., & Grieve, D. J. (2016). Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages. Basic Research in Cardiology,111, 1.PubMedCrossRef
28.
Hsu, C.-P., Zhai, P., Yamamoto, T., Maejima, Y., Matsushima, S., Hariharan, N., et al. (2010). Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation,122, 2170–2182.PubMedPubMedCentralCrossRef
29.
Mao, S., Chen, P., Li, T., Guo, L., & Zhang, M. (2018). Tongguan capsule mitigates post-myocardial infarction remodeling by promoting autophagy and inhibiting apoptosis: Role of Sirt1. Frontiers in Physiology,9, 589.PubMedPubMedCentralCrossRef
30.
Minematsu, T., Huang, L., Ibuki, A., Nakagami, G., Akase, T., Sugama, J., et al. (2012). Altered expression of matrix metalloproteinases and their tissue inhibitors in matured rat adipocytes in vitro. Biological Research for Nursing,14, 242–249.PubMedCrossRef
31.
Bai, J., Zhang, N., Hua, Y., Wang, B., Ling, L., Ferro, A., et al. (2013). Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts. PLoS ONE,8, e72120.PubMedPubMedCentralCrossRef
32.
Sun, L., Liu, C., Xu, X., Ying, Z., Maiseyeu, A., Wang, A., et al. (2013). Ambient fine particulate matter and ozone exposures induce inflammation in epicardial and perirenal adipose tissues in rats fed a high fructose diet. Particle and Fibre Toxicology,10, 43.PubMedPubMedCentralCrossRef
33.
Seo, S., Lee, M.-S., Chang, E., Shin, Y., Oh, S., Kim, I.-H., et al. (2015). Rutin increases muscle mitochondrial biogenesis with AMPK activation in high-fat diet-induced obese rats. Nutrients,7, 8152–8169.PubMedPubMedCentralCrossRef
34.
Yan, N., Liu, Y., Liu, S., Cao, S., Wang, F., Wang, Z., et al. (2016). Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Molecular Neurobiology,53, 4449–4460.PubMedCrossRef
35.
Fusegawa, Y., Hashizume, H., Okumura, T., Deguchi, Y., Shina, Y., Ikari, Y., et al. (2006). Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability. Thrombosis Research,117, 615–622.PubMedCrossRef
36.
Zhao, H., Zhang, J., & Hong, G. (2018). Minocycline improves cardiac function after myocardial infarction in rats by inhibiting activation of PARP-1. Biomedicine & Pharmacotherapy,97, 1119–1124.CrossRef
37.
Harvey, A. P., & Grieve, D. J. (2014). Reactive oxygen species (ROS) signaling in cardiac remodeling and failure. In I. Laher (Ed.), Systems biology of free radicals and antioxidants (pp. 951–992). Berlin: Springer.CrossRef
38.
Bai, S., He, C., Zhang, K., Ding, X., Zeng, Q., Wang, J., et al. (2019). Effects of dietary inclusion of Radix Bupleuri and Radix Astragali extracts on the performance, intestinal inflammatory cytokines expression, and hepatic antioxidant capacity in broilers exposed to high temperature. Animal Feed Science and Technology,259, 114288.CrossRef
39.
Shou, Y., Li, N., Li, L., Borowitz, J. L., & Isom, G. E. (2002). NF-κB-mediated up-regulation of Bcl-XS and Bax contributes to cytochrome c release in cyanide-induced apoptosis. Journal of Neurochemistry,81, 842–852.PubMedCrossRef
40.
Gupta, S., Afaq, F., & Mukhtar, H. (2002). Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene,21, 3727.PubMedCrossRef
41.
Matsuzawa, A., Nishitoh, H., Tobiume, K., Takeda, K., & Ichijo, H. (2002). Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endoplasmic reticulum stress-induced apoptosis: Advanced findings from ASK1 knockout mice. Antioxidants and Redox Signaling,4, 415–425.PubMedCrossRef
42.
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S.-I., Frye, R. A., Pandita, T. K., et al. (2001). hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell,107, 149–159.PubMedCrossRef
43.
Chong, A.-Y., & Lip, G. Y. (2002). Hormone replacement therapy and cardiovascular risk. Treatments in Endocrinology,1, 95–103.PubMedCrossRef
44.
Kim, H. J., Joe, Y., Yu, J. K., Chen, Y., Jeong, S. O., Mani, N., et al. (2015). Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. Biochimica et Biophysica Acta,1852, 1550–1559.PubMedCrossRef
45.
Di, W., Lv, J., Jiang, S., Lu, C., Yang, Z., Ma, Z., et al. (2018). PGC-1: The energetic regulator in cardiac metabolism. Current Issues in Molecular Biology,28, 29–46.PubMedCrossRef
46.
Fredj, S., Bescond, J., Louault, C., Delwail, A., & LecronPotreau, J. C. D. (2005). Role of interleukin-6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation. Journal of Cellular Physiology,204, 428–436.PubMedCrossRef
47.
Pellman, J., Zhang, J., & Sheikh, F. (2016). Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems. Journal of Molecular and Cellular Cardiology,94, 22–31.PubMedPubMedCentralCrossRef
48.
Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research,74, 184–195.PubMedCrossRef
49.
Gong, D., Shi, W., Yi, S.-J., Chen, H., Groffen, J., & Heisterkamp, N. (2012). TGFβ signaling plays a critical role in promoting alternative macrophage activation. BMC Immunology,13, 31.PubMedPubMedCentralCrossRef
50.
DeLeon-Pennell, K. Y., Meschiari, C. A., Jung, M., & Lindsey, M. L. (2017). Matrix metalloproteinases in myocardial infarction and heart failure. Progress in Molecular Biology and Translational Science,147, 75–100.PubMedPubMedCentralCrossRef
51.
Kawano, S., Kubota, T., Monden, Y., Tsutsumi, T., Inoue, T., Kawamura, N., et al. (2006). Blockade of NF-κB improves cardiac function and survival after myocardial infarction. American Journal of Physiology-Heart and Circulatory Physiology,291, H1337–H1344.PubMedCrossRef
52.
Guo, C., Huang, T., Chen, A., Chen, X., Wang, L., Shen, F., et al. (2016). Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages. Brazilian Journal of Medical and Biological Research,49(12), e5826.PubMedPubMedCentralCrossRef
53.
Iwaya, C., Nomiyama, T., Komatsu, S., Kawanami, T., Tsutsumi, Y., Hamaguchi, Y., et al. (2017). Exendin-4, a glucagonlike peptide-1 receptor agonist, attenuates breast cancer growth by inhibiting NF-κ B activation. Endocrinology,158, 4218–4232.PubMedCrossRef
54.
De Flora, A., Zocchi, E., Guida, L., Franco, L., & Bruzzone, S. (2004). Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system. Annals of the New York Academy of Sciences,1028, 176–191.PubMed
55.
Kauppinen, T. M., Gan, L., & Swanson, R. A. (2013). Poly(ADP-ribose) polymerase-1-induced NAD+ depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation. Biochimica et Biophysica Acta,1833, 1985–1991.PubMedPubMedCentralCrossRef
Metadata
Title
Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism
Authors
Refaat A. Eid
Samah A. Alharbi
Attalla Farag El-kott
Samy M. Eleawa
Mohamed Samir Ahmed Zaki
Fahmy El-Sayed
Muhammad Alaa Eldeen
Hussain Aldera
Abd Al-Rahman Salem Al-Shudiefat
Publication date
01-08-2020
Publisher
Springer US
Published in
Cardiovascular Toxicology / Issue 4/2020
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI
https://doi.org/10.1007/s12012-020-09567-5

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