J. Pharm. Pharmacogn. Res., vol. 10, no. 6, pp. 1076-1086, November-December 2022.

DOI: https://doi.org/10.56499/jppres22.1517_10.6.1076

Original Article

Effect of Rhodomyrtus tomentosa Hassk. on HIF1α and VEGF expressions on hypertension placental

[Efecto de Rhodomyrtus tomentosa Hassk. sobre las expresiones de HIF1α y VEGF sobre la hipertensión placentaria]

Putri Cahaya Situmorang^1*, Syafruddin Ilyas¹, Doni Aldo Samuel Siahaan¹, Martina Restuati², Endang Ratna Sari¹, Chairunisa Chairunisa¹, Muhammad Faldhy Maliki¹

¹Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, Indonesia.

²Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Negeri Medan, Medan, Indonesia.

*E-mail: putri.cahaya@usu.ac.id

Abstract

Context: HIF1α and VEGF are proteins marker oxidative stress and a decrease in placental growth factor (PlGF). Decreasing of HIF1α and VEGF in rats displayed poor trophoblast differentiation, placental abnormalities, and fetal mortality. Rhodomyrtus tomentosa is a flowering plant in the Myrtaceae family that has the potential to be a source of health-promoting chemicals.

Aims: To analyze HIF1α and VEGF in serum and hypertension placental tissue after giving Rhodomyrtus tomentosa (RHO) leaves extract.

Methods: Six treatments were given to the rats that were identified as being pregnant and pregnant rats with hypertension were given RHO with three doses: (a) normal pregnant rats (control); (b) hypertensive rats; (c) hypertensive rats + 100 mg/kg BW of RHO; (d) hypertensive rats +200 mg/kg BW of RHO; and (e) hypertensive rats + 400 mg/kg BW of RHO and (f) hypertensive rats + nifedipine. Under ketamine anesthesia, pregnant rats were removed on their 20^th day of gestation. Immunohistochemistry and ELISA were used to assess HIF1α and VEGF protein expression.

Results: There was a significant difference (p<0.01) in the expression of HIF1α and VEGF in the labyrinthine zone and yolk sac of the rat placenta between the normal (C-) and hypertensive (C+) groups. HIF1α and VEGF expression decreased when RHO was administered at doses ranging from 100 to 400 mg/kg BW. However, there was no significant change (p>0.05) in VEGF expression in the basal zone of the rat placenta across all groups.

Conclusions: Rhodomyrtus tomentosa leaves extract decreases HIF1α and VEGF expressions in serum and repairs the tissue of the placenta’s labyrinth, basal, and yolk sacs.

Keywords: basal zone; HIF1α; hypertension; labyrinth zone; plant extract; VEGF; yolk sac.

Resumen

Contexto: HIF1α y VEGF son proteínas marcadoras de estrés oxidativo y disminución del factor de crecimiento placentario (PlGF). La disminución de HIF1α y VEGF en ratas mostró una pobre diferenciación del trofoblasto, anomalías placentarias y mortalidad fetal. Rhodomyrtus tomentosa es una planta con flores de la familia Myrtaceae que tiene el potencial de ser una fuente de productos químicos que promueven la salud.

Objetivos: Analizar HIF1α y VEGF en suero y tejido placentario hipertenso después de administrar extracto de hojas de Rhodomyrtus tomentosa (RHO).

Métodos: Se administraron seis tratamientos a las ratas que se identificaron como preñadas ya las ratas preñadas con hipertensión se les administró RHO con tres dosis: (a) ratas preñadas normales (control); (b) ratas hipertensas; (c) ratas hipertensas + 100 mg/kg de peso corporal de RHO; (d) ratas hipertensas +200 mg/kg de peso corporal de RHO; y (e) ratas hipertensas + 400 mg/kg de peso corporal de RHO y (f) ratas hipertensas + nifedipina. Bajo anestesia con ketamina, las ratas preñadas se extrajeron en su día 20 de gestación. Se usaron inmunohistoquímica y ELISA para evaluar la expresión de proteínas HIF1α y VEGF.

Resultados: Hubo diferencia significativa (p<0.01) en la expresión de HIF1α y VEGF en la zona laberíntica y saco vitelino de la placenta de rata entre los grupos normal (C-) e hipertenso (C+). La expresión de HIF1α y VEGF disminuyó cuando se administró RHO en dosis que oscilaron entre 100 y 400 mg/kg de peso corporal. Sin embargo, no hubo cambios significativos (p>0,05) en la expresión de VEGF en la zona basal de la placenta de rata en todos los grupos.

Conclusiones: El extracto de hojas de Rhodomyrtus tomentosa disminuye las expresiones de HIF1α y VEGF en suero y repara el tejido del laberinto, basal y saco vitelino de la placenta.

Palabras Clave: extracto de plantas; HIF1α; hipertensión; saco vitelino; VEGF; zona basal; zona laberinto.

Citation Format: Situmorang PC, Ilyas S, Siahaan DAS, Restuati M, Sari ER, Chairunisa C, Maliki MF (2022) Effect of Rhodomyrtus tomentosa Hassk. on HIF1α and VEGF expressions on hypertension placental. J Pharm Pharmacogn Res 10(6): 1076–1086. https://doi.org/10.56499/jppres22.1517_10.6.1076

References

Belkacemi L, Desai M, Nelson DM, Ross MG (2011) Altered mitochondrial apoptotic pathway in placentas from undernourished rat gestations. Am J Physiol Regul Integr Comp Physiol 301(6): R1599-R1615. https://doi.org/10.1152/ajpregu.00100.2011

Braunthal S, Brateanu A (2019) Hypertension in pregnancy: Pathophysiology and treatment. SAGE Open Med 7: 2050312119843700. https://doi.org/10.1177/2050312119843700

Fan X, Rai A, Kambham N, Sung JF, Singh N, Petitt M, Dhal S, Agrawal R, Sutton RE, Druzin ML, Gambhir SS, Ambati BK, Cross JC, Nayak NR (2014) Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications. J Clin Invest 124(11): 4941-4952. https://doi.org/10.1172/JCI76864

Fan X, Muruganandan S, Shallie PD, Dhal S, Petitt M, Nayak NR (2021) VEGF maintains maternal vascular space homeostasis in the mouse placenta through modulation of trophoblast giant cell functions. Biomolecules 11(7): 1062. https://doi.org/10.3390/biom11071062

Furukawa S, Tsuji N, Sugiyama A (2019) Morphology and physiology of rat placenta for toxicological evaluation. J Toxicol Pathol 32(1): 1–17. https://doi.org/10.1293/tox.2018-0042

Furukawa S, Kuroda Y, Sugiyama A (2014) A comparison of the histological structure of the placenta in experimental animals. J Toxicol Pathol 27(1): 11–18. https://doi.org/10.1293/tox.2013-0060

Hemberger M (2012) Health during pregnancy and beyond: Fetal trophoblast cells as chief co-ordinators of intrauterine growth and reproductive success. Ann Med44: 325–337. https://doi.org/10.3109/07853890.2012.663930

Hutagaol JM, Bintang, Hidayat B (2021) Identification of highland peat vegetation in the sub-district of Lintong Nihuta, Humbang Hasundutan Regency, North Sumatera, Indonesia. IOP Conf Series: Earth Environ Sci 912: 012027 https://doi.org/10.1088/1755-1315/912/1/012027

Ilyas S, Murdela F, Hutahaean S, Situmorang PC (2019) The effect of haramounting leaf ethanol extract (Rhodomyrtus tomentosa (Aiton) Hassk.) on the number of leukocyte type and histology of mice pulmo (Mus musculus L.) exposed to electronic cigarette. Open Access Maced J Med Sci 7(11): 1750-1756. https://doi.org/10.3889/oamjms.2019.467

Ilyas S, Situmorang PC (2021) Role of heat shock protein 70 (HSP-70) after giving nanoherbal haramonting (Rhodomyrtus tomentosa) in preeclamptic rats. Pak J Biol Sci 24: 139-145. https://doi.org/10.3923/pjbs.2021.139.145

Irianti E, Ilyas S, Hutahaean S, Rosidah R, Situmorang PC (2020) Placental histological on preeclamptic rats (Rattus norvegicus) after administration of nanoherbal haramonting (Rhodomyrtus tomentosa). Res J Pharm Technol 13(8): 3879-3882. https://doi.org/10.5958/0974-360X.2020.00686.1

Kametas NA, Nzelu D, Nicolaides KH (2022) Chronic hypertension and superimposed preeclampsia: Screening and diagnosis. Am J Obstet Gynecol 226(2S): S1182-S1195. https://doi.org/10.1016/j.ajog.2020.11.029

Kubo T, Fujie K, Yamashita M, Misu Y (1981) Antihypertensive effects of nifedipine on conscious normotensive and hypertensive rats. J Pharmacobiodyn 4(4): 294-300. https://doi.org/10.1248/bpb1978.4.294

Kurnianto A, Kurniadi Sunjaya D, Ruluwedrata Rinawan F, Hilmanto D (2020) Prevalence of hypertension and its associated factors among Indonesian adolescents. Int J Hypertens 2020: 4262034. https://doi.org/10.1155/2020/4262034

Li Q, Yao B, Endler L, Chen L, Shibasaki F, Cheng H (2018) Int6/eIF3e silencing promotes placenta angiogenesis in a rat model of pre-eclampsia. Sci Rep 8(1): 8944. https://doi.org/10.1038/s41598-018-27296-2

Malnou EC, Umlauf D, Mouysset M, Cavaillé J (2019) Imprinted microRNA gene clusters in the evolution, development, and functions of mammalian placenta.Front Genet 9: 706. https://doi.org/10.3389/fgene.2018.00706

Maria JM, Warrington JP (2019) Cerebral blood flow regulation in pregnancy, hypertension, and hypertensive disorders of pregnancy. Brain Sci 9(9): 224. https://doi.org/10.3390/brainsci9090224

Morfoisse F, Renaud E, Hantelys F, Prats AC, Garmy-Susini B (2014) Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis. Mol Cell Oncol 1(1): e29907. https://doi.org/10.4161/mco.29907

Opichka MA, Rappelt MW, Gutterman DD, Grobe JL, McIntosh JJ (2021) Vascular dysfunction in preeclampsia. Cells 10(11): 3055. https://doi.org/10.3390/cells10113055

Pandey AK, Singhi EK, Arroyo JP, Ikizler TA, Gould ER, Brown J, Beckman JA, Harrison DG, Moslehi J (2018) Mechanisms of VEGF (vascular endothelial growth factor) inhibitor-associated hypertension and vascular disease. Hypertension 71(2): e1-e8. https://doi.org/10.1161/HYPERTENSIONAHA.117.10271

Phipps EA, Benzing TR, Thandani TR, Karumanchi SA (2019) Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol 15(5): 275–289. https://doi.org/10.1038/s41581-019-0119-6

Reshef T (2012) The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis. Biol Reprod 87(6): 134. https://doi.org/10.1095/biolreprod.112.102723

Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD (2010) Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker. Semin Nephrol 30(6): 591-601. https://doi.org/10.1016/j.semnephrol.2010.09.007

Ross C, Boroviak TE (2020) Origin and function of the yolk sac in primate embryogenesis. Nature Comm 11: 3760. https://doi.org/10.1038/s41467-020-17575-w

Salles AMR, Galvao TF, Silva MT, Motta LCD, Pereira MG (2012) Antioxidants for preventing preeclampsia: A systematic review. ScientificWorldJournal 2012: 243476. https://doi.org/10.1100/2012/243476

Sarkar AA, Sabatino JA, Sugrue KF, Zohn IE (2016) Abnormal labyrinthine zone in the Hectd1-null placenta. Placenta 38: 16-23. https://doi.org/10.1016/j.placenta.2015.12.002

Siragher E, Sferruzzi-Perri AN (2021) Placental hypoxia: What have we learnt from small animal models. Placenta113: 29-47. https://doi.org/10.1016/j.placenta.2021.03.01

Situmorang PC, Ilyas S (2018) Description of testis histology of Mus musculus after giving nano herbal Rhodomyrtus tomentosa (haramonting). Asian J Pharm Clin Res 11: 461-463. https://doi.org/10.22159/ajpcr.2018.v11i11.29042

Situmorang PC, Ilyas S, Hutahaean S, Rosidah R (2020) Components and acute toxicity of nanoherbal haramonting (Rhodomyrtus tomentosa). J Herbmed Pharmacol 10: 139-148. https://doi.org/10.34172/jhp.2021.15

Situmorang PC, Ilyas S, Hutahaean S, Rosidah R (2021) Histological changes in placental rat apoptosis via FasL and cytochrome c by the nano-herbal Zanthoxylum acanthopodium. Saudi J Bio Sci 28(5): 3060–3068. https://doi.org/10.1016/j.sjbs.2021.02.047

Situmorang PC, Syahputra RA, Simanullang RH (2022) EGFL7 and HIF-1a expression on human trophoblast placental by Rhodomyrtus tomentosa and Zanthoxylum acanthopodium. Pak J Biol Sci 25(2): 123-130. https://doi.org/10.3923/pjbs.2022.123.130

Strowitzki C, Taylor (2019) Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: Unique or ubiquitous? Cells 8(5): 384. https://doi.org/10.3390/cells8050384

Villanueva-Toledo JR, Chale-Dzul J, Castillo-Bautista C, Olivera-Castillo LA, Rangel-Méndez LA, Graniel-Sabido MJ, Moo-Puc RE (2020) Hepatoprotective effect of an ethanol extract of Tradescantia pallida against CCl4-induced liver damage in rats. S Afr J Bot 13: 444–450. https://doi.org/10.1016/j.sajb.2020.09.031

Vo T, Ngo D (2019) The health beneficial properties of Rhodomyrtus tomentosa as potential functional food. Biomolecules 9(2): 76. https://doi.org/10.3390/biom9020076

Wang HJ, Lu CK, Chen WC, Chen AC, Ueng YF (2019) Shenmai-Yin decreased the clearance of nifedipine in rats: The involvement of time-dependent inhibition of nifedipine oxidation. J Food Drug Anal 27(1): 284-294. https://doi.org/10.1016/j.jfda.2018.10.005

Zhang B, Kim MY, Elliot G, Zhou Y, Zhao G, Li D, Lowdon RF, Gormley M, Kapidzic M, Robinson JF, McMaster MT, Hong C, Mazor T, Hamilton E, Sears RL, Pehrsson EC, Marra MA, Jones SJM, Bilenky M, Hirst M, Wang T, Costello JF, Fisher SJ (2021) Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease. Dev Cell 56(9): 1238–1252.e5. https://doi.org/10.1016/j.devcel.2021.04.001

Zhang YB, Li W, Jiang L, Yang L, Chen NH, Wu ZN, Li YL, Wang GC (2018) Cytotoxic and anti-inflammatory active phloroglucinol derivatives from Rhodomyrtus tomentosa. Phytochemistry 153: 111–119. https://doi.org/10.1016/j.phytochem.2018.05.018.

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