Eucommia ulmoides extract attenuates angiotensin II-induced cardiac microvascular endothelial cell dysfunction by inactivating p53
DOI:
https://doi.org/10.1590/s2175-97902023e22473Keywords:
Eucommia ulmoides extract, Angiotensin II, Cardiac microvascular endothelial cell, p53 activation, DysfunctionAbstract
Angiotensin II (AngII) causes endothelial dysfunction. Eucommia ulmoides extract (EUE) is documented to manipulate AngII, but its impact on cardiac microvascular endothelial cell (CMVEC) function remains unknown. This study determines the effects of EUE on AngII-treated CMVECs. CMVECs were treated with different concentrations of AngII or EUE alone and/or the p53 protein activator, WR-1065, before AngII treatment, followed by examinations of the apoptotic, migratory, proliferative, and angiogenic capacities and nitric oxide (NO), p53, von Willebrand factor (vWF), endothelin (ET)-1, endothelial NO synthase (eNOS), manganese superoxide dismutase (MnSOD), hypoxia-inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) levels. AngII induced CMVEC dysfunction in a concentration-dependent manner. EUE enhanced the proliferative, migratory, and angiogenic capacities and NO, MnSOD, and eNOS levels but repressed apoptosis and vWF and ET-1 levels in AngII-induced dysfunctional CMVECs. Moreover, AngII increased p53 mRNA levels, p-p53 levels in the nucleus, and p53 protein levels in the cytoplasm and diminishes HIF-1α and VEGF levels in CMVECs; however, these effects were counteracted by EUE treatment. Moreover, WR-1065 abrogated the mitigating effects of EUE on AngII-induced CMVEC dysfunction by activating p53 and decreasing HIF-1α and VEGF expression. In conclusion, EUE attenuates AngII-induced CMVEC dysfunction by upregulating HIF-1α and VEGF levels via p53 inactivation.
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Cao P, Ma B, Sun D, Zhang W, Qiu J, Qin L, et al. Hsa_ Circ_0003410 Promotes Hepatocellular Carcinoma Progression by Increasing the Ratio of M2/M1 Macrophages through the Mir-139-3p/Ccl5 Axis. Cancer Sci. 2022;113(2):634-47.
Cao Y, Jiang Z, Zeng Z, Liu Y, Gu Y, Ji Y, et al. Bcl-2 silencing attenuates hypoxia-induced apoptosis resistance in pulmonary microvascular endothelial cells. Apoptosis. 2016;21(1):69-84.
Chen G, Xu C, Gillette TG, Huang T, Huang P, Li Q, et al. Cardiomyocyte-derived small extracellular vesicles can signal enos activation in cardiac microvascular endothelial cells to protect against ischemia/reperfusion injury. Theranostics. 2020;10(25):11754-74.
Chen Y, Pan R, Zhang J, Liang T, Guo J, Sun T, et al. Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy Via AKT/ mTOR/NF-Kappab signaling in pressure overload-induced rats. J Ethnopharmacol. 2021;272:113920.
Dang Y, Ling S, Duan J, Ma J, Ni R, Xu JW. Bavachalcone-induced manganese superoxide dismutase expression through the amp-activated protein kinase pathway in human endothelial cells. Pharmacology. 2015;95(3-4):105-10.
Duan M, Yuan Y, Liu C, Cai Z, Xie Q, Hu T, et al. Indigo fruits ingredient, aucubin, protects against LPS-induced cardiac dysfunction in mice. J Pharmacol Exp Ther. 2019;371(2):348-59.
Ames MK, Atkins CE, Pitt B. Erratum for the Renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med. 2019;33(5):2551.
Fan L, Zhou W, Zhang L, Jiang D, Zhao Q, Liu L. Sitagliptin protects against Hypoxia/Reoxygenation (H/R)-induced cardiac microvascular endothelial cell injury. Am J Transl Res. 2019;11(4):2099-107.
Glover M, Hebert VY, Nichols K, Xue SY, Thibeaux TM, Zavecz JA, et al. Overexpression of mitochondrial antioxidant Manganese Superoxide Dismutase (Mnsod) provides protection against Azt- or 3tc-induced endothelial dysfunction. Antiviral Res. 2014;111:136-42.
Godo S, Shimokawa H. Endothelial functions. Arterioscler Thromb Vasc Biol. 2017;37(9):e108-e14.
Guan A, Gong H, Ye Y, Jia J, Zhang G, Li B, et al. Regulation of P53 by Jagged1 Contributes to Angiotensin Ii-Induced Impairment of Myocardial Angiogenesis. PLoS One. 2013;8(10):e76529.
He X, Wang J, Li M, Hao D, Yang Y, Zhang C, et al. Eucommia ulmoides oliv.: Ethnopharmacology, phytochemistry and pharmacology of an important Traditional Chinese Medicine. J Ethnopharmacol . 2014;151(1):78-92.
Ishimitsu A, Tojo A, Satonaka H, Ishimitsu T. Eucommia ulmoides (Tochu) and its extract geniposidic acid reduced blood pressure and improved renal hemodynamics. Biomed Pharmacother. 2021;141:111901.
Kim DY, Piao J, Hong HS. Substance-P inhibits cardiac microvascular endothelial dysfunction caused by high glucose-induced oxidative stress. Antioxidants (Basel). 2021;10(7):1084.
Lee GH, Lee HY, Choi MK, Choi AH, Shin TS, Chae HJ. Eucommia ulmoides leaf (EUL) extract enhances no production in ox-LDL-treated human endothelial cells. Biomed Pharmacother. 2018;97:1164-72.
Lee MK, Kim MJ, Cho SY, Park SA, Park KK, Jung UJ, et al. Hypoglycemic effect of Du-Zhong (Eucommia Ulmoides Oliv.) leaves in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract. 2005;67(1):22-8.
Lee SH, Kang JH, Ha JS, Lee JS, Oh SJ, Choi HJ, et al. Transglutaminase 2-mediated p53 depletion promotes angiogenesis by increasing HIF-1alpha-p300 binding in renal cell carcinoma. Int J Mol Sci. 2020;21(14):5042.
Leite AR, Borges-Canha M, Cardoso R, Neves JS, Castro-Ferreira R, Leite-Moreira A. Novel biomarkers for evaluation of endothelial dysfunction. Angiology. 2020;71(5):397-410.
Li DX, Chen W, Jiang YL, Ni JQ, Lu L. Antioxidant protein peroxiredoxin 6 suppresses the vascular inflammation, oxidative stress and endothelial dysfunction in angiotensin II-induced endotheliocyte. Gen Physiol Biophys. 2020;39(6):545-55.
Li F, Wang J, Song Y, Shen D, Zhao Y, Li C, et al. Qiliqiangxin alleviates Ang II-Induced CMECS apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis. Life Sci. 2021;273:119239.
Li G, Qiu Z, Li C, Zhao R, Zhang Y, Shen C, et al. Exosomal MiR-29a in cardiomyocytes induced by angiotensin II regulates cardiac microvascular endothelial cell proliferation, migration and angiogenesis by targeting VEGFA. Curr Gene Ther. 2022;
Li LM, Zheng B, Zhang RN, Jin LS, Zheng CY, Wang C, et al. Chinese medicine Tongxinluo increases tight junction protein levels by inducing KLF5 expression in microvascular endothelial cells. Cell Biochem Funct. 2015;33(4):226-34.
Li X, Gui Z, Liu H, Qian S, Jia Y, Luo X. Remifentanil pretreatment ameliorates H/R-induced cardiac microvascular endothelial cell dysfunction by regulating the Pi3k/Akt/Hif-1alpha signaling pathway. Bioengineered. 2021;12(1):7872-81.
Li ZY, Gu J, Yan J, Wang JJ, Huang WH, Tan ZR, et al. Hypertensive cardiac remodeling effects of lignan extracts from eucommia ulmoides oliv. Bark--a famous traditional Chinese medicine. Am J Chin Med. 2013;41(4):801-15.
Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, et al. Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal mirna-21-5p-targeted CDIP1 silencing to improve angiogenesis following myocardial infarction. Theranostics . 2021;11(1):268-91.
Liu B, Li CP, Wang WQ, Song SG, Liu XM. Lignans extracted from eucommia ulmoides oliv. protects against ages-induced retinal endothelial cell injury. Cell Physiol Biochem. 2016;39(5):2044-54.
Liu C, Guo FF, Xiao JP, Wei JY, Tang LY, Yang HJ. [Research Advances in Chemical Constituents and Pharmacological Activities of Different Parts of Eucommia Ulmoides]. Zhongguo Zhong Yao Za Zhi. 2020;45(3):497-512.
Liu E, Han L, Wang J, He W, Shang H, Gao X, et al. eucommia ulmoides bark protects against renal injury in cadmium-challenged rats. J Med Food. 2012;15(3):307-14.
Liu Y, Zou J, Li B, Wang Y, Wang D, Hao Y, et al. Runx3 modulates hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial Cells. Int J Mol Med. 2017;40(1):65-74.
Long L, Zhang X, Wen Y, Li J, Wei L, Cheng Y, et al. Qingda granule attenuates angiotensin II-induced renal apoptosis and activation of the P53 pathway. Front Pharmacol. 2021;12:770863.
Luo LF, Wu WH, Zhou YJ, Yan J, Yang GP, Ouyang DS. Antihypertensive effect of eucommia ulmoides oliv. extracts in spontaneously hypertensive rats. J Ethnopharmacol . 2010;129(2):238-43.
Luo X, Wu J, Li Z, Jin W, Zhang F, Sun H, et al. Safety Evaluation of Eucommia Ulmoides Extract. Regul Toxicol Pharmacol. 2020;118:104811.
Melincovici CS, Bosca AB, Susman S, Marginean M, Mihu C, Istrate M, et al. Vascular Endothelial Growth Factor (Vegf) - Key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455-67.
Men H, Cai H, Cheng Q, Zhou W, Wang X, Huang S, et al. the regulatory roles of p53 in cardiovascular health and disease. Cell Mol Life Sci . 2021;78(5):2001-18.
Nagpal I, Yuan ZM. The Basally Expressed P53-Mediated Homeostatic Function. Front Cell Dev Biol. 2021;9(775312.
Naryzhny SN, Legina OK. Structural-Functional Diversity of P53 Proteoforms. Biomed Khim. 2019;65(4):263-76.
Park SA, Choi MS, Jung UJ, Kim MJ, Kim DJ, Park HM, et al. Eucommia ulmoides oliver leaf extract increases endogenous antioxidant activity in type 2 Diabetic mice. J Med Food . 2006;9(4):474-9.
Qi J, Wang F, Yang P, Wang X, Xu R, Chen J, et al. Mitochondrial Fission Is Required for Angiotensin Ii-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-P53 Signaling Pathway. Front Pharmacol. 2018;9:176.
Rana NK, Singh P, Koch B. Cocl2 simulated hypoxia induce cell proliferation and alter the expression pattern of hypoxia associated genes involved in angiogenesis and apoptosis. Biol Res. 2019;52(1):12.
Rodkin S, Khaitin A, Pitinova M, Dzreyan V, Guzenko V, Rudkovskii M, et al. The localization of P53 in the crayfish mechanoreceptor neurons and its role in axotomy-induced death of satellite glial cells remote from the axon transection site. J Mol Neurosci. 2020;70(4):532-41.
Si R, Zhang Q, Tsuji-Hosokawa A, Watanabe M, Willson C, Lai N, et al. overexpression of p53 due to excess protein o-glcnacylation is associated with coronary microvascular disease in Type 2 diabetes. Cardiovasc Res. 2020;116(6):1186-98.
Song J, Huang S, Wang K, Li W, Pao L, Chen F, et al. Long Non-Coding Rna Meg3 Attenuates the Angiotensin Ii-Induced Injury of Human Umbilical Vein Endothelial Cells by Interacting with P53. Front Genet. 2019;10:78.
Wang JY, Yuan Y, Chen XJ, Fu SG, Zhang L, Hong YL, et al. Extract from eucommia ulmoides oliv. ameliorates arthritis via regulation of inflammation, synoviocyte proliferation and osteoclastogenesis in vitro and in vivo. J Ethnopharmacol . 2016;194:609-16.
Wang Y, Fan Y, Song Y, Han X, Fu M, Wang J, et al. Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating Ptp1b/Pi3k/Akt pathway. In Vitro Cell Dev Biol Anim. 2019;55(10):801-11.
Wu QQ, Xiao Y, Duan MX, Yuan Y, Jiang XH, Yang Z, et al. Aucubin protects against pressure overload-induced cardiac remodelling via the Beta3 -Adrenoceptor-Neuronal Nos cascades. Br J Pharmacol. 2018;175(9):1548-66.
Yang Y, Zou P, He L, Shao J, Tang Y, Li J. CBL Aggravates Ang II-induced cardiac hypertrophy via the VHL/HIF-1alpha pathway. Exp Cell Res. 2021;405(2):112730.
Zeng ZM, Du HY, Xiong L, Zeng XL, Zhang P, Cai J, et al. Brca1 protects cardiac microvascular endothelial cells against irradiation by regulating P21-mediated cell cycle arrest. Life Sci . 2020;244:117342.
Zhang D, Lv FL, Wang GH. Effects of HIF-1alpha on diabetic retinopathy angiogenesis and VEGF expression. Eur Rev Med Pharmacol Sci. 2018;22(16):5071-76.
Zhang X, Qi Z, Yin H, Yang G. Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4- and HIF-1alpha-mediated regulation of apoptosis and autophagy. Theranostics . 2019;9(4):1096-114.
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