Abstract
The cardioprotective impact of Amaranthus viridis methanolic extracts (AVMEs) and its active phytoconstituent kaempferol on isoproterenol (ISO)-induced cardiotoxicity in a rat model was examined in this study, along with some of the underlying molecular mechanisms. Prior to administering ISO (20 mg/100 mg BW) on the 31st and 32nd day to induce myocardial infarction (MI), the rats were pre-treated with AVME (250 mg/kg BW) and kaempferol (50 mg/kg BW) for 30 days each. Following ISO administration, we examined the effects of AVME and kaempferol on hemodynamic parameters, oxidative stress, and apoptotic markers in the heart tissue. The study’s findings showed that by reducing lipid peroxidation, vascular O2•̅, and NoX generation and enhancing the activities of antioxidant enzymes, AVME and kaempferol relieved the rats from hemodynamic depression and further protected them from free radical–mediated cardiac injury. Additionally, pre-treatment with AVME and kaempferol increased tissue levels of heme oxygenase (HO)-1 and nuclear factor erythroid-2-related factor-2 (Nrf-2) while de-escalating those of toll-like receptor-4 (TLR-4) and caspase-3. Furthermore, AVME and kaempferol down-regulated the expression of matrix metalloproteinases (MMP-2 and MMP-9), caspase-3, B cell lymphoma protein-2, Bcl-2-associated X, and TLR-4 while activating the Nrf-2/HO-1 pathway. Overall, the findings of the present investigation showed that up-regulation of the Nrf-2/HO-1 and concomitant down-regulation of MMP/Bax/Bcl-2/TLR-4 signaling pathways had significant ameliorative effects against ISO-induced MI by decreasing oxidative stress and apoptosis.
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The data that support the findings of this study are available on reasonable request from the corresponding author, Roja Rani A.
References
Abdelzaher WY, Ahmed SM, Welson NN, Alsharif KF, Batiha GE, Labib DAA (2021) Dapsone ameliorates isoproterenol-induced myocardial infarction via Nrf2/ HO-1; TLR4/ TNF-α signaling pathways and the suppression of oxidative stress, inflammation, and apoptosis in rats. Front Pharmacol 12:669679. https://doi.org/10.3389/fphar.2021.669679
Abukhalil MH, Hussein OE, Aladaileh SH, Althunibat OY, Al-Amarat W, Saghir SA, Alfwuaires MA, Algefare AI, Alanazi KM, Al-Swailmi FK, Kamel EM, Mahmoud AM (2021) Visnagin prevents isoproterenol-induced myocardial injury by attenuating oxidative stress and inflammation and upregulating Nrf2 signaling in rats. J Biochem Mol Toxicol 35:e22906. https://doi.org/10.1002/jbt.22906
Boarescu PM, Chirilă I, Bulboacă AE, Bocșan IC, Pop RM, Gheban D, Bolboacă SD (2019) Effects of curcumin nanoparticles in isoproterenol-induced myocardial infarction. Oxid Med Cell Longev 2019:7847142. https://doi.org/10.1155/2019/7847142
Brahmanaidu P, Uddandrao VVS, Sasikumar V, Naik RR, Pothani S, Begum MS, Rajeshkumar MP, Varatharaju C, Meriga B, Rameshreddy P, Kalaivani A, Saravanan G (2017) Reversal of endothelial dysfunction in aorta of streptozotocin-nicotinamide-induced type-2 diabetic rats by S-Allylcysteine. Mol Cell Biochem 432:25–32. https://doi.org/10.1007/s11010-017-2994-0
Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310. https://doi.org/10.1016/s0076-6879(78)52032-6
Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, Martinez-Avila N, Martinez-Fierro ML (2020) The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21:9739. https://doi.org/10.3390/ijms21249739
Filipský T, Zatloukalová L, Mladěnka P, Hrdina R (2012) Acute initial haemodynamic changes in a rat isoprenaline model of cardiotoxicity. Hum Exp Toxicol 31:830–843. https://doi.org/10.1177/0960327112438927
Govindasami S, Uddandrao VVS, Raveendran N, Sasikumar V (2020) Therapeutic potential of biochanin-A against isoproterenol-induced myocardial infarction in rats. Cardiovasc Hematol Agents Med Chem 18:31–36. https://doi.org/10.2174/1871525718666200206114304
Hatok J, Racay P (2016) Bcl-2 family proteins: master regulators of cell survival. Biomol Concepts 7:259–270. https://doi.org/10.1515/bmc-2016-0015
Ibrahim MA, Abdelzaher WY, Ibrahim YF, Ahmed AF, Welson NN, Al-Rashed S, Batiha GE, Abdel-Aziz AM (2021) Diacerein protects rats with liver ischemia/reperfusion damage: down-regulation of TLR4/ NFκ-B signaling pathway. Biomed Pharmacother 134:111063. https://doi.org/10.1016/j.biopha.2020.111063
Jansy Isabella Rani A, Sathibabu Uddandrao VV, Sangeethadevi G, Saravanan G, Chandrasekaran P, Sengottuvelu S, Tamilmani P, Sethumathi PP, Vadivukkarasi S (2021) Biochanin A attenuates obesity cardiomyopathy in rats by inhibiting oxidative stress and inflammation through the Nrf-2 pathway. Arch Physiol Biochem 1–16. https://doi.org/10.1080/13813455.2021.1874017
Kavita P, Puneet G (2017) Rediscovering the therapeutic potential of Amaranthus species: a review. Egypt J Basic Appl Sci 4:196–205. https://doi.org/10.1016/j.ejbas.2017.05.001
Kibel A, Lukinac AM, Dambic V, Juric I, Selthofer-Relatic K (2020) Oxidative stress in ischemic heart disease. Oxid Med Cell Longev 6627144. https://doi.org/10.1155/2020/6627144.
Li H, Yang H, Wang D, Zhang L, Ma T (2020) Peroxiredoxin2 (Prdx2) Reduces oxidative stress and apoptosis of myocardial cells induced by acute myocardial infarction by inhibiting the TLR4/nuclear factor kappa B (NF-κB) signaling pathway. Med Sci Monit 26:e926281. https://doi.org/10.12659/MSM.926281.
Li H, Song F, Duan LR, Sheng JJ, Xie YH, Yang Q, Chen Y, Dong QQ, Zhang BL, Wang SW (2016) Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: Roles of Nrf2/HO-1 and PI3K/Akt pathway. Sci Rep 6:23693. https://doi.org/10.1038/srep23693
Ma S, Ma J, Tu Q, Zheng C, Chen Q, Lv W (2020) Isoproterenol increases left atrial fibrosis and susceptibility to atrial fibrillation by inducing atrial ischemic infarction in rats. Front Pharmacol 1:493. https://doi.org/10.3389/fphar.2020.00493
McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5:a008656. https://doi.org/10.1101/cshperspect.a008656
Mohamed ME, Abduldaium MS, Younis NS (2021) Cardioprotective effect of linalool against isoproterenol-induced myocardial infarction. Life (basel, Switzerland) 11:120. https://doi.org/10.3390/life11020120
Obeidat HM, Althunibat OY, Alfwuaires MA, Aladaileh SH, Algefare AI, Almuqati AF, Alasmari F, Aldal’in HK, Alanezi AA, Alsuwayt B, Abukhalil MH (2022) Cardioprotective effect of taxifolin against isoproterenol-induced cardiac injury through decreasing oxidative stress, inflammation, and cell death, and activating Nrf2/HO-1 in mice. Biomolecules 12:1546. https://doi.org/10.3390/biom12111546
Pavithra K, Sathibabu Uddandrao VV, Chandrasekaran P, Brahmanaidu P, Sengottuvelu S, Vadivukkarasi S, Saravanan G (2020) Phenolic fraction extracted from Kedrostis foetidissima leaves ameliorated isoproterenol-induced cardiotoxicity in rats through restoration of cardiac antioxidant status. J Food Biochem 44:e13450. https://doi.org/10.1111/jfbc.13450
Rong N, Yang R, Ibrahim IAA, Zhang W (2023) Cardioprotective role of scopoletin on isoproterenol-induced myocardial infarction in rats. Appl Biochem Biotechnol 195:919–932. https://doi.org/10.1007/s12010-022-04123-z
Sangeethadevi G, VVS U, Jansy Isabella RAR, Saravanan G, Ponmurugan P, Chandrasekaran P, Sengottuvelu S, Vadivukkarasi S (2022) Attenuation of lipid metabolic abnormalities, proinflammatory cytokines, and matrix metalloproteinase expression by biochanin-A in isoproterenol-induced myocardial infarction in rats. Drug Chem Toxicol 45:1951–1962. https://doi.org/10.1080/01480545.2021.1894707
Saravanan G, Ponmurugan P (2011) Ameliorative potential of S-allyl cysteine on oxidative stress in STZ induced diabetic rats. Chem Biol Interact 189:100–106. https://doi.org/10.1016/j.cbi.2010.10.001
Sathibabu Uddandrao VV, Brahmanaidu P, Nivedha PR, Vadivukkarasi S, Saravanan G (2018) Beneficial role of some natural products to attenuate the diabetic cardiomyopathy through Nrf2 pathway in cell culture and animal models. Cardiovasc Toxicol 18:199–205. https://doi.org/10.1007/s12012-017-9430-2
Sathibabu Uddandrao VV, Brahmanaidu P, Ravindarnaik R, Suresh P, Vadivukkarasi S, Saravanan G (2019) Restorative potentiality of S-allylcysteine against diabetic nephropathy through attenuation of oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic rats. Eur J Nutr 58:2425–2437. https://doi.org/10.1007/s00394-018-1795-x
Sathibabu Uddandrao VV, Sethumathi PP, Parim Brahma Naidu, Vadivukkarasi S, Mustapha Sabana Begum, Saravanan G (2022) Ameliorative potential of biochanin-A against dexamethasone induced hypertension through modulation of relative mRNA and protein expressions in experimental rats, advancements in cardiovascular research and therapeutics: molecular and nutraceutical perspectives 1:156. https://doi.org/10.2174/9789815050837122010011
Uddandrao VVS, Parim B, Singaravel S, Ponnusamy P, Ponnusamy C, Sasikumar V, Saravanan G (2022) Polyherbal formulation ameliorates diabetic cardiomyopathy through attenuation of cardiac inflammation and oxidative stress via NF-κB/Nrf-2/HO-1 pathway in diabetic rats. J Cardiovasc Pharmacol 79:e75–e86. https://doi.org/10.1097/FJC.0000000000001167
Wu X, Wei J, Yi Y, Gong Q, Gao J (2022) Activation of Nrf2 signaling: A key molecular mechanism of protection against cardiovascular diseases by natural products. Front Pharmacol 13:1057918. https://doi.org/10.3389/fphar.2022.1057918
Xing Z, Yang C, He J, Feng Y, Li X, Peng C, Li D (2022) Cardioprotective effects of aconite in isoproterenol-induced myocardial infarction in rats. Oxid Med Cell Longev 2022:1090893. https://doi.org/10.1155/2022/1090893
Zhou Y, Li M, Song J, Shi Y, Qin X, Gao Z, Lv Y, Du G (2020) The cardioprotective effects of the new crystal form of puerarin in isoproterenol-induced myocardial ischemia rats based on metabolomics. Sci Rep 10:17787. https://doi.org/10.1038/s41598-020-74246-y
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This research received funding from DST-SERB Project, UGC-Centre with Potential for Excellence in Particular Area (CPEPA) by RRA and the infrastructure facilities was partially supported by DST PURSE 2.0, Department of Science and Technology, Government of India. The fellowship was provided by UGC-RGNF, New Delhi to RKN (Fellowship No: 202021-NFST-TEL-00696; dt: 20-09-2021).
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The protocol of the study was approved by the Institutional Animal Ethical Committee, Jeeva Life Sciences, Hyderabad, Telangana, India (Approval No: CPCSEA/IAEC/JLS/14/02/21/80). All the experiments were carried out as per the guidelines provided by Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.
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Krishna, P.S., N, R.K., Swathi et al. Amaranthus viridis methanolic extract and its active compound kaempferol ameliorate myocardial infarction induced by isoproterenol through decreasing oxidative stress and cell death via Nrf-2/HO-1 and MMP/Bax/Bcl-2/TLR-4 pathways in rats. Comp Clin Pathol 32, 661–670 (2023). https://doi.org/10.1007/s00580-023-03474-1
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DOI: https://doi.org/10.1007/s00580-023-03474-1