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Food Science and Human Wellness 2024, 13(3): 1465-1474 https://doi.org/10.26599/FSHW.2022.9250123
Research Article | Open Access | Issue | Published: 08 February 2024

Punicalagin prevents obesity-related cardiac dysfunction through promoting DNA demethylation in mice

Show Author's Information Shengjie Peia,b,  Run Liua,b,  Qingqing Mac,  Peng Jiangd,  Xin Hea,b,  Zhongshi Qia,b,  Jiacheng Fanga,b,  Xu Yange,  Zirui Yaoa,b,  Xiaoqian Liua,  Xianfeng Jinga,b,  Lei Chena,b( ),  Duo Lia,b,( )
Institute of Nutrition & Health, Qingdao University, Qingdao 266071, China
School of Public Health, Qingdao University, Qingdao 266071, China
Central Laboratory, Guizhou Aerospace Hospital, Zunyi 563000, China
Health Centers of Licha Town, Qingdao 266071, China
College of Computer Science and Technology, Qingdao University, Qingdao 266071, China

Peer review under responsibility of Tsinghua University Press.

Keywords:
Mitochondrial function, DNA demethylation, Obesity-related cardiac dysfunction, Punicalagin, Ten-eleven translocation family enzymes
Cite this article:
Pei S, Liu R, Ma Q, et al. Punicalagin prevents obesity-related cardiac dysfunction through promoting DNA demethylation in mice. Food Science and Human Wellness, 2024, 13(3): 1465-1474. https://doi.org/10.26599/FSHW.2022.9250123
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Abstract Full text Electronic supplementary material About this article

The aim of this study was to investigate whether punicalagin (PU) could prevent obesity-related cardiac dysfunction by promoting DNA demethylation, and to explore its possible mechanism. C57BL/6J mice were fed with standard diet, high-fat diet (HFD), HFD supplemented with resveratrol, low-dose PU (LPU) and high-dose PU (HPU) for 8 weeks. Compared with HFD group, body weight was signif icantly lower in PU treatment groups, number of cardiomyocytes and the protein level of myosin heavy chain 7B were signif icantly higher in PU treatment groups. Levels of 5-hydroxymethylcytosine and 5-formylcytosine were signif icantly lower in HFD group than in other groups. Compared with the HFD group, the protein level of ten-eleven translocation enzyme (TET) 2 was significantly higher in PU treatment groups, p-AMP-activated protein kinase (AMPK) was signif icantly higher in LPU group. Levels of total antioxidant capacity and the protein levels of complexes Ⅱ/Ⅲ/Ⅴ, oxoglutarate dehydrogenase, succinate dehydrogenase B and fumarate hydrolase were signif icantly lower in HFD group than PU treatment group. The ratio of (succinic acid + fumaric acid)/α-ketoglutarate was signif icantly higher in HFD group than other groups. In conclusion, PU up-regulated TETs enzyme activities and TET2 protein stability through alleviating mitochondrial dysfunction and activating AMPK, so as to promote DNA demethylation, thus preventing obesity-related cardiac dysfunction.


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Electronic supplementary material
About this article

Punicalagin prevents obesity-related cardiac dysfunction through promoting DNA demethylation in mice

Show Author's information Shengjie Peia,b, Run Liua,b, Qingqing Mac, Peng Jiangd, Xin Hea,b, Zhongshi Qia,b, Jiacheng Fanga,b, Xu Yange, Zirui Yaoa,b, Xiaoqian Liua, Xianfeng Jinga,b, Lei Chena,b( ), Duo Lia,b,( )
Institute of Nutrition & Health, Qingdao University, Qingdao 266071, China
School of Public Health, Qingdao University, Qingdao 266071, China
Central Laboratory, Guizhou Aerospace Hospital, Zunyi 563000, China
Health Centers of Licha Town, Qingdao 266071, China
College of Computer Science and Technology, Qingdao University, Qingdao 266071, China

Peer review under responsibility of Tsinghua University Press.

Abstract

The aim of this study was to investigate whether punicalagin (PU) could prevent obesity-related cardiac dysfunction by promoting DNA demethylation, and to explore its possible mechanism. C57BL/6J mice were fed with standard diet, high-fat diet (HFD), HFD supplemented with resveratrol, low-dose PU (LPU) and high-dose PU (HPU) for 8 weeks. Compared with HFD group, body weight was signif icantly lower in PU treatment groups, number of cardiomyocytes and the protein level of myosin heavy chain 7B were signif icantly higher in PU treatment groups. Levels of 5-hydroxymethylcytosine and 5-formylcytosine were signif icantly lower in HFD group than in other groups. Compared with the HFD group, the protein level of ten-eleven translocation enzyme (TET) 2 was significantly higher in PU treatment groups, p-AMP-activated protein kinase (AMPK) was signif icantly higher in LPU group. Levels of total antioxidant capacity and the protein levels of complexes Ⅱ/Ⅲ/Ⅴ, oxoglutarate dehydrogenase, succinate dehydrogenase B and fumarate hydrolase were signif icantly lower in HFD group than PU treatment group. The ratio of (succinic acid + fumaric acid)/α-ketoglutarate was signif icantly higher in HFD group than other groups. In conclusion, PU up-regulated TETs enzyme activities and TET2 protein stability through alleviating mitochondrial dysfunction and activating AMPK, so as to promote DNA demethylation, thus preventing obesity-related cardiac dysfunction.

Keywords: Mitochondrial function, DNA demethylation, Obesity-related cardiac dysfunction, Punicalagin, Ten-eleven translocation family enzymes

References(52)

[1]

M. Nakamura, J. Sadoshima, Cardiomyopathy in obesity, insulin resistance and diabetes, J. Physiol. 598 (2020) 2977-2993. https://doi.org/10.1113/JP276747.
DOI Google Scholar
[2]

Z.G. Ma, C.Y. Kong, P. Song, et al., Geniposide protects against obesity-related cardiac injury through AMPKα- and Sirt1-dependent mechanisms, Oxid. Med. Cell. Longev. 2018 (2018) 6053727. https://doi.org/10.1155/2018/6053727.
DOI Google Scholar
[3]

M.E. Hall, J.B. Cohen, J.D. Ard, et al., Weight-loss strategies for prevention and treatment of hypertension: a scientific statement from the American Heart Association, Hypertension 78 (2021) e38-e50. https://doi.org/10.1161/HYP.0000000000000202.
DOI Google Scholar
[4]

J.A. Levinson, V. Sarda, K. Sonneville, et al., Diet pill and laxative use for weight control and subsequent incident eating disorder in US young women: 2001-2016, Am. J. Public. Health. 110 (2020) 109-111. https://doi.org/10.2105/AJPH.2019.305390.
DOI Google Scholar
[5]

S. Fang, J. Li, Y. Xiao, et al., Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development, Nat. Commun. 10 (2019) 4297. https://doi.org/10.1038/s41467-019-12325-z.
DOI Google Scholar
[6]

X. Wu, Y. Zhang. TET-mediated active DNA demethylation: mechanism, function and beyond, Nat. Rev. Genet. 18 (2017) 517-534. https://doi.org/10.1038/nrg.2017.33.
DOI Google Scholar
[7]

M. Małodobra-Mazur, A. Alama, D. Bednarska-Chabowska, et al., Obesityinduced insulin resistance via changes in the DNA methylation profile of insulin pathway genes, Adv. Clin. Exp. Med. 28 (2019) 1599-1607. https://doi.org/10.17219/acem/110321.
DOI Google Scholar
[8]

X. Wang, A.H. Liu, Z.W. Jia, et al., Genome-wide DNA methylation patterns in coronary heart disease, Herz. 43 (2018) 656-662. https://doi.org/10.1007/s00059-017-4616-8.
DOI Google Scholar
[9]

D. Jiang, M. Sun, L. You, et al., DNA methylation and hydroxymethylation are associated with the degree of coronary atherosclerosis in elderly patients with coronary heart disease, Life Sci. 224 (2019) 241-248. https://doi.org/10.1016/j.lfs.2019.03.021.
DOI Google Scholar
[10]

X. Li, F. Xie, J. Jin, et al., TET2-mediated spatiotemporal changes of 5-hydroxymethylcytosine during organogenesis in the late mouse fetus, Anat. Rec (Hoboken). 302 (2019) 954-963. https://doi.org/10.1002/ar.24009.
DOI Google Scholar
[11]

X. Xu, X. Tan, B. Tampe, et al., Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis, Cardiovasc. Res. 105 (2015) 279-291. https://doi.org/10.1093/cvr/cvv015.
DOI Google Scholar
[12]

M. Xiao, H. Yang, W. Xu, et al., Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors, Genes. Dev. 26 (2012) 1326-1338. https://doi.org/10.1101/gad.191056.112.
DOI Google Scholar
[13]

D. Wu, D. Hu, H. Chen, et al., Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer, Nature 559 (2018) 637-641. https://doi.org/10.1038/s41586-018-0350-5.
DOI Google Scholar
[14]

M. Ding, Y. Wang, D. Sun, et al., Punicalagin pretreatment attenuates myocardial ischemia-reperfusion injury via activation of AMPK, Am. J. Chin. Med. 45 (2017) 53-66. https://doi.org/10.1142/S0192415X17500057.
DOI Google Scholar
[15]

K. Cao, J. Xu, W. Pu, et al., Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation, Sci. Rep. 5 (2015) 14014. https://doi.org/10.1038/srep14014.
DOI Google Scholar
[16]

X. Liu, K. Cao, W. Lv, et al., Punicalagin attenuates endothelial dysfunction by activating FoxO1, a pivotal regulating switch of mitochondrial biogenesis, Free. Radic. Biol. Med. 135 (2019) 251-260. https://doi.org/10.1016/j.freeradbiomed.2019.03.011.
DOI Google Scholar
[17]

B. Cerdá, J.J. Cerón, F.A.Tomás-Barberán, et al., Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 days is not toxic, J. Agric. Food. Chem. 51 (2003) 3493-3501. https://doi.org/10.1021/jf020842c.
DOI Google Scholar
[18]

N.P. Seeram, S.M. Henning, Y. Zhang, et al., Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours, J. Nutr. 136 (2006) 2481-2485. https://doi.org/10.1093/jn/136.10.2481.
DOI Google Scholar
[19]

L. Chen, L. Liu, C. Li, et al., A mix of apple pomace polysaccharide improves mitochondrial function and reduces oxidative stress in the liver of high-fat diet-induced obese mice, Mol. Nutr. Food. Res. 61 (2017). https://doi.org/10.1002/mnfr.201600433.
DOI Google Scholar
[20]

R. Liu, L. Chen, Z. Wang, et al., Downregulation of the DNA 5-hydroxymethylcytosine is involved in mitochondrial dysfunction and neuronal impairment in high fat diet-induced diabetic mice, Free. Radic. Biol. Med. 148 (2020) 42-51. https://doi.org/10.1016/j.freeradbiomed.2019.12.042.
DOI Google Scholar
[21]

R. Liu, L. Chen, Y. Wang, et al., High ratio of ω-3/ω-6 polyunsaturated fatty acids targets mTORC1 to prevent high-fat diet-induced metabolic syndrome and mitochondrial dysfunction in mice, J. Nutr. Biochem. 79 (2020) 108330. https://doi.org/10.1016/j.jnutbio.2019.108330.
DOI Google Scholar
[22]

J. Li, H. Wu, Y. Liu, et al., High fat diet induced obesity model using four strains of mice: Kunming, C57BL/6, BALB/c and ICR, Exp. Anim. 69 (2020) 326-335. https://doi.org/10.1538/expanim.19-0148.
DOI Google Scholar
[23]

X. Fang, J. Robinson, J. Wang-Hu, et al., cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes, Am. J. Physiol. Cell. Physiol. 309 (2015) C425-C436. https://doi.org/10.1152/ajpcell.00058.2015.
DOI Google Scholar
[24]

J. Shi, J. Xu, Y. Chen, et al., The concurrence of DNA methylation and demethylation is associated with transcription regulation, Nat. Commun. 12 (2021) 5285. https://doi.org/10.1038/s41467-021-25521-7.
DOI Google Scholar
[25]

S. Pei, H. Zhao, L. Chen, et al., Preventive effect of ellagic acid on cardiac dysfunction in diabetic mice through regulating DNA hydroxymethylation, J. Agric. Food. Chem. 70 (2022) 1902-1910. https://doi.org/10.1021/acs.jafc.1c07574.
DOI Google Scholar
[26]

R. Zhao, X. Long, J. Yang, et al., Pomegranate peel polyphenols reduce chronic low-grade inflammatory responses by modulating gut microbiota and decreasing colonic tissue damage in rats fed a high-fat diet, Food Funct.10 (2019), 8273-8285. https://doi.org/10.1039/c9fo02077b.
DOI Google Scholar
[27]

B. Kang, C.Y. Kim, J. Hwang, et al., Punicalagin, a pomegranate-derived ellagitannin, suppresses obesity and obesity-induced inflammatory responses via the Nrf2/Keap1 signaling pathway, Mol. Nutr. Food. Res. 63 (2019) e1900574. https://doi.org/10.1002/mnfr.201900574.
DOI Google Scholar
[28]

L.M. Yu, X. Dong, X.D. Xue, et al., Protection of the myocardium against ischemia/reperfusion injury by punicalagin through an SIRT1-NRF-2-HO-1-dependent mechanism, Chem. Biol. Interact. 306 (2019) 152-162. https://doi.org/10.1016/j.cbi.2019.05.003.
DOI Google Scholar
[29]

L. Zhu, C. Li, Q. Liu, et al., Molecular biomarkers in cardiac hypertrophy, J. Cell. Mol. Med. 23 (2019) 1671-1677. https://doi.org/10.1111/jcmm.14129.
DOI Google Scholar
[30]

D.G. Edmondson, G.E. Lyons, J.F. Martin, et al., Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis, Development 120 (1994) 1251-1263. https://doi.org/10.1242/dev.120.5.1251.
DOI Google Scholar
[31]

Q. Lin, J. Schwarz, C. Bucana, et al., Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C, Science 276 (1997) 1404-1407. https://doi.org/10.1126/science.276.5317.1404.
DOI Google Scholar
[32]

Z.Y. Zhang, X.H. Liu, W.C. Hu, et al., The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes, Am. J. Physiol. Heart. Circ. Physiol. 298 (2010) H1499-1509. https://doi.org/10.1152/ajpheart.00980.2009.
DOI Google Scholar
[33]

P. Chen, Z. Li, J. Nie, et al., MYH7B variants cause hypertrophic cardiomyopathy by activating the CaMK-signaling pathway, Sci. China Life Sci. 63 (2020) 1347-1362. https://doi.org/10.1007/s11427-019-1627-y.
DOI Google Scholar
[34]

W. Mizunoya, S. Okamoto, H. Miyahara, et al., Fast-to-slow shift of muscle fiber-type composition by dietary apple polyphenols in rats: impact of the low-dose supplementation, Anim. Sci. J. 88 (2017) 489-499. https://doi.org/10.1111/asj.12655.
DOI Google Scholar
[35]

F. Ciccarone, S. Castelli, L. Ioannilli, et al., High dietary fat intake affects DNA methylation/hydroxymethylation in mouse heart: epigenetic hints for obesity-related cardiac dysfunction, Mol. Nutr. Food Res. 63 (2019) e1800970. https://doi.org/10.1002/mnfr.201800970.
DOI Google Scholar
[36]

C.M. Greco, P. Kunderfranco, M. Rubino, et al., DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy, Nat. Commun. 7 (2016) 12418. https://doi.org/10.1038/ncomms12418.
DOI Google Scholar
[37]

P. Xie, L.Q. Zang, X.K. Li, et al., An epigenetic view of developmental diseases: new targets, new therapies, World J. Pediat. 12 (2016) 291-297. https://doi.org/10.1007/s12519-016-0020-3.
DOI Google Scholar
[38]

Y. Tsuboi, H. Yamada, E. Munetsuna, et al., Global DNA hypermethylation in peripheral blood mononuclear cells and cardiovascular disease risk: a population-based propensity score-matched cohort study, J. Epidemiol. Community Health 75 (2021) 890-895. https://doi.org/10.1136/jech-2020-215382.
DOI Google Scholar
[39]

M. Bachman, S. Uribe-Lewis, X. Yang, et al., 5-Formylcytosine can be a stable DNA modification in mammals, Nat. Chem. Biol. 11 (2015) 555-557. https://doi.org/10.1038/nchembio.1848.
DOI Google Scholar
[40]

A. Vujic, E.L. Robinson, M. Ito, et al., Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B, J. Mol. Cell. Cardiol. 82 (2015) 174-183. https://doi.org/10.1016/j.yjmcc.2015.03.007.
DOI Google Scholar
[41]

A. Madsen, G. Höppner, J. Krause, et al., An important role for DNMT3A-mediated dna methylation in cardiomyocyte metabolism and contractility, Circulation 142 (2020) 1562-1578. https://doi.org/10.1161/CIRCULATIONAHA.119.044444.
DOI Google Scholar
[42]

H. Tao, W. Xu, W. Qu, et al., Loss of ten-eleven translocation 2 induces cardiac hypertrophy and fibrosis through modulating ERK signaling pathway, Hum. Mol. Genet. 30 (2021) 865-879. https://doi.org/10.1093/hmg/ddab046.
DOI Google Scholar
[43]

K.E. Szulwach, X. Li, Y. Li, et al., 5-hmC-Mediated epigenetic dynamics during postnatal neurodevelopment and aging, Nat. Neurosci. 14 (2011),1607-1616. https://doi.org/10.1038/nn.2959.
DOI Google Scholar
[44]

Q. Yang, X. Liang, X. Sun, et al., AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the PRDM16 promoter and brown adipogenesis, Cell. Metab. 24 (2016) 542-554. https://doi.org/10.1016/j.cmet.2016.08.010.
DOI Google Scholar
[45]

C.R. Lindholm, R.L. Ertel, J.D. Bauwens, et al., A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats, J. Physiol. Biochem. 69 (2013) 165-175. https://doi.org/10.1007/s13105-012-0199-2.
DOI Google Scholar
[46]

K. Cao, K. Wang, M. Yang, et al., Punicalagin improves hepatic lipid metabolism via modulation of oxidative stress and mitochondrial biogenesis in hyperlipidemic mice, Food Funct. 11 (2020) 9624-9633. https://doi.org/10.1039/d0fo01545h.
DOI Google Scholar
[47]

W. Sun, C. Yan, B. Frost, et al., Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats, Sci. Rep. 6 (2016) 34246. https://doi.org/10.1038/srep34246.
DOI Google Scholar
[48]

I. Martínez-Reyes, N.S. Chandel, Mitochondrial TCA cycle metabolites control physiology and disease, Nat. Commun. 11 (2020) 102. https://doi.org/10.1038/s41467-019-13668-3.
DOI Google Scholar
[49]

Y. Luo, J. Ma, W. Lu. The significance of mitochondrial dysfunction in cancer, Int. J. Mol. Sci. 21 (2020) 5598. https://doi.org/10.3390/ijms21165598.
DOI Google Scholar
[50]

A. Vujic, A.N.M. Koo, H.A. Prag, et al., Mitochondrial redox and TCA cycle metabolite signaling in the heart, Free Radic. Bio. Med. 166 (2021) 287-296. https://doi.org/10.1016/j.freeradbiomed.2021.02.041.
DOI Google Scholar
[51]

Y. Zhou, F. Zhang, H. Jiang, et al., Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1, Exp. Ther. Med. 22 (2021) 1072. https://doi.org/10.3892/etm.2021.10506.
DOI Google Scholar
[52]

X. He, S. Pei, X. Meng, et al., Punicalagin attenuates neuronal apoptosis by upregulating 5-hydroxymethylcytosine in the diabetic mouse brain, J. Agric. Food. Chem. 70 (2022) 4995-5004. https://doi.org/10.1021/acs.jafc.2c00863.
DOI Google Scholar
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Received: 27 September 2022
Revised: 25 October 2022
Accepted: 08 November 2022
Published: 08 February 2024
Issue date: May 2024

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© 2024 Beijing Academy of Food Sciences. Publishing services by Tsinghua University Press.

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Acknowledgment

This work was supported by the Natural Science Foundation of Shandong Province (ZR2020QH294 and ZR2021QH342).

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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