Acrolein-induced atherosclerosis via AMPK/SIRT1-CLOCK/BMAL1 pathway and the protection from intermittent fasting

Abstract

The circadian clock is crucial for the progression of cardiovascular diseases. Our previous studies showed that acrolein, an environmental pollutant, exacerbated atherosclerosis by reducing CLOCK/BMAL1 levels and disrupting circadian rhythm; in contrast, intermittent fasting (IF), a dietary regimen, ameliorated acrolein-induced atherosclerosis. In the current study, mice were administered acrolein at a dose of 3 mg/(kg·day) via drinking water and subjected to IF for 18 h (from 0:00 to 18:00). We observed that IF reduced the formation of aortic lesions accelerated by acrolein in ApoE^−/− mice. Upon exposure to acrolein, the expression of RelA, Il1b, and Tnf increased in the liver and heart tissues, but these changes were reversed by IF treatment. Notably, IF treatment upregulated the expression of adenosine monophosphate (AMP)-activated protein kinase catalytic subunit alpha-1 (AMPKα1), p-AMPKα1, and sirtuin 1 (SIRT1), while inhibiting acrolein-induced mitogen-activated protein kinase (MAPK) activation. Additionally, the expression of circadian genes Clock/Bmal1 was suppressed and disrupted by acrolein, whereas IF restored their expression. Moreover, consistent with the in vivo findings, short-term starvation in vitro, as a fasting cell model, alleviated the dysregulation of CLOCK/BMAL1 and upregulated SIRT1 expression by modulating the AMPK and reactive oxygen species (ROS)-MAPK pathways activated by acrolein. In summary, we demonstrated that IF suppressed the ROS-MAPK pathway but activated the AMPK pathway to enhance the expression of circadian clock genes, thereby ameliorating acrolein-induced atherogenesis, which may shed light on strategies for preventing cardiovascular diseases.

Keywords

intermittent fasting / acrolein / circadian rhythm / AMPK / SIRT1 / MAPK

Fundings

The present study was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Key Project of Jiangsu Commission of Health (Grant No. ZD2022012).

Acknowledgments

We gratefully acknowledge our professors and colleagues at the institutions for their technical and experimental support.

References

[1] Kaufman JD, Adar SD, Barr RG, et al. Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): A longitudinal cohort study[J]. Lancet, 2016, 388 (10045): 696-704. doi: 10.1016/S0140-6736(16)00378-0

[2] de Bont J, Jaganathan S, Dahlquist M, et al. Ambient air pollution and cardiovascular diseases: An umbrella review of systematic reviews and meta-analyses[J]. J Intern Med, 2022, 291 (6): 779-800. doi: 10.1111/joim.13467

[3] DeJarnett N, Conklin DJ, Riggs DW, et al. Acrolein exposure is associated with increased cardiovascular disease risk[J]. J Am Heart Assoc, 2014, 3 (4): e000934. doi: 10.1161/JAHA.114.000934

[4] Moghe A, Ghare S, Lamoreau B, et al. Molecular mechanisms of acrolein toxicity: Relevance to human disease[J]. Toxicol Sci, 2015, 143 (2): 242-255. doi: 10.1093/toxsci/kfu233

[5] Zirak MR, Mehri S, Karimani A, et al. Mechanisms behind the atherothrombotic effects of acrolein, a review[J]. Food Chem Toxicol, 2019, 129: 38-53. doi: 10.1016/j.fct.2019.04.034

[6] Chen L, Wu X, Zeb F, et al. Acrolein-induced apoptosis of smooth muscle cells through NEAT1-Bmal1/Clock pathway and a protection from asparagus extract[J]. Environ Pollut, 2020, 258: 113735. doi: 10.1016/j.envpol.2019.113735

[7] Xu Y, Wu L, Chen A, et al. Protective effects of olive leaf extract on acrolein-exacerbated myocardial infarction via an endoplasmic reticulum stress pathway[J]. Int J Mol Sci, 2018, 19 (2): 493. doi: 10.3390/ijms19020493

[8] Zhou Y, Jin W, Wu Q, et al. Acrolein: Formation, health hazards and its controlling by dietary polyphenols[J]. Crit Rev Food Sci Nutr, 2023. doi: 10.1080/10408398.2023.2214625

[9] Vasim I, Majeed CN, DeBoer MD. Intermittent fasting and metabolic health[J]. Nutrients, 2022, 14 (3): 631. doi: 10.3390/nu14030631

[10] Varady KA. Intermittent versus daily calorie restriction: Which diet regimen is more effective for weight loss?[J]. Obes Rev, 2011, 12 (7): e593-e601. doi: 10.1111/j.1467-789X.2011.00873.x

[11] Malinowski B, Zalewska K, Węsierska A, et al. Intermittent fasting in cardiovascular disorders—an overview[J]. Nutrients, 2019, 11 (3): 673. doi: 10.3390/nu11030673

[12] Chen Y, Su J, Yan Y, et al. Intermittent fasting inhibits high-fat diet-induced atherosclerosis by ameliorating hypercholesterolemia and reducing monocyte chemoattraction[J]. Front Pharmacol, 2021, 12: 719750. doi: 10.3389/fphar.2021.719750

[13] Schilperoort M, van den Berg R, Bosmans LA, et al. Disruption of circadian rhythm by alternating light-dark cycles aggravates atherosclerosis development in APOE^*3-Leiden. CETP mice[J]. J Pineal Res, 2020, 68 (1): e12614. doi: 10.1111/jpi.12614

[14] Huang T, Mariani S, Redline S. Sleep irregularity and risk of cardiovascular events: The multi-ethnic study of atherosclerosis[J]. J Am Coll Cardiol, 2020, 75 (9): 991-999. doi: 10.1016/j.jacc.2019.12.054

[15] Kervezee L, Shechter A, Boivin DB. Impact of shift work on the circadian timing system and health in women[J]. Sleep Med Clin, 2018, 13 (3): 295-306. doi: 10.1016/j.jsmc.2018.04.003

[16] Crnko S, Du Pré BC, Sluijter JPG, et al. Circadian rhythms and the molecular clock in cardiovascular biology and disease[J]. Nat Rev Cardiol, 2019, 16 (7): 437-447. doi: 10.1038/s41569-019-0167-4

[17] Sun L, Ma J, Turck CW, et al. Genome-wide circadian regulation: A unique system for computational biology[J]. Comput Struct Biotechnol J, 2020, 18: 1914-1924. doi: 10.1016/j.csbj.2020.07.002

[18] Xie M, Tang Q, Nie J, et al. BMAL1-downregulation aggravates Porphyromonas gingivalis-induced atherosclerosis by encouraging oxidative stress[J]. Circ Res, 2020, 126 (6): e15-e29. doi: 10.1161/CIRCRESAHA.119.315502

[19] Wu X, Chen L, Zeb F, et al. Clock-Bmal1 mediates MMP9 induction in acrolein-promoted atherosclerosis associated with gut microbiota regulation[J]. Environ Pollut, 2019, 252: 1455-1463. doi: 10.1016/j.envpol.2019.06.042

[20] Ge Y, Zhou M, Chen C, et al. Role of AMPK mediated pathways in autophagy and aging[J]. Biochimie, 2022, 195: 100-113. doi: 10.1016/j.biochi.2021.11.008

[21] Masri S. Sirtuin-dependent clock control: New advances in metabolism, aging and cancer[J]. Curr Opin Clin Nutr Metab Care, 2015, 18 (6): 521-527. doi: 10.1097/MCO.0000000000000219

[22] Li H, Kilgallen AB, Münzel T, et al. Influence of mental stress and environmental toxins on circadian clocks: Implications for redox regulation of the heart and cardioprotection[J]. Br J Pharmacol, 2020, 177 (23): 5393-5412. doi: 10.1111/bph.14949

[23] Sundar IK, Sellix MT, Rahman I. Redox regulation of circadian molecular clock in chronic airway diseases[J]. Free Radic Biol Med, 2018, 119: 121-128. doi: 10.1016/j.freeradbiomed.2017.10.383

[24] Duan L, Zhao Y, Jia J, et al. Myeloid-restricted CD68 deficiency attenuates atherosclerosis via inhibition of ROS-MAPK-apoptosis axis[J]. Biochim Biophys Acta Mol Basis Dis, 2023, 1869 (5): 166698. doi: 10.1016/j.bbadis.2023.166698

[25] Adafer R, Messaadi W, Meddahi M, et al. Food timing, circadian rhythm and chrononutrition: A systematic review of time-restricted eating's effects on human health[J]. Nutrients, 2020, 12 (12): 3770. doi: 10.3390/nu12123770

[26] Di Tano M, Raucci F, Vernieri C, et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers[J]. Nat Commun, 2020, 11 (1): 2332. doi: 10.1038/s41467-020-16243-3

[27] Wolf D, Ley K. Immunity and inflammation in atherosclerosis[J]. Circ Res, 2019, 124 (2): 315-327. doi: 10.1161/CIRCRESAHA.118.313591

[28] Matsubara Y, Kiyohara H, Teratani T, et al. Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases[J]. Neuropharmacology, 2022, 205: 108915. doi: 10.1016/j.neuropharm.2021.108915

[29] González A, Hall MN, Lin SC, et al. AMPK and TOR: The yin and yang of cellular nutrient sensing and growth control[J]. Cell Metab, 2020, 31 (3): 472-492. doi: 10.1016/j.cmet.2020.01.015

[30] Pan X, Mota S, Zhang B. Circadian clock regulation on lipid metabolism and metabolic diseases[M]//Jiang X. Lipid Transfer in lipoprotein metabolism and cardiovascular disease. Singapore: Springer, 2020: 53-66.

[31] Alfarhan M, Jafari E, Narayanan SP. Acrolein: A potential mediator of oxidative damage in diabetic retinopathy[J]. Biomolecules, 2020, 10 (11): 1579. doi: 10.3390/biom10111579

[32] Rom O, Korach-Rechtman H, Hayek T, et al. Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: Protective role for the polyphenol-rich pomegranate juice[J]. Arch Toxicol, 2017, 91 (4): 1709-1725. doi: 10.1007/s00204-016-1859-8

[33] Hong J, Song Y, Xie J, et al. Acrolein promotes aging and oxidative stress via the stress response factor DAF-16/FOXO in Caenorhabditis elegans[J]. Foods, 2022, 11 (11): 1590. doi: 10.3390/foods11111590

[34] Jiang L, Luo S, Qiu T, et al. Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis[J]. Toxicol Mech Methods, 2021, 31 (9): 680-689. doi: 10.1080/15376516.2021.1953204

[35] Yu J, Jiang Q, Liu N, et al. Apigenin and apigenin-7, 4'-O-dioctanoate protect against acrolein-aggravated inflammation via inhibiting the activation of NLRP3 inflammasome and HMGB1/MYD88/NF-κB signaling pathway in Human umbilical vein endothelial cells (HUVEC)[J]. Food Chem Toxicol, 2022, 168: 113400. doi: 10.1016/j.fct.2022.113400

[36] Srivastava S, Sithu SD, Vladykovskaya E, et al. Oral exposure to acrolein exacerbates atherosclerosis in apoE-null mice[J]. Atherosclerosis, 2011, 215 (2): 301-308. doi: 10.1016/j.atherosclerosis.2011.01.001

[37] D'Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection[J]. Antioxid Redox Signal, 2018, 28 (8): 711-732. doi: 10.1089/ars.2017.7178

[38] Jordan SD, Lamia KA. AMPK at the crossroads of circadian clocks and metabolism[J]. Mol Cell Endocrinol, 2013, 366 (2): 163-169. doi: 10.1016/j.mce.2012.06.017

[39] Imai SI, Guarente L. NAD⁺ and sirtuins in aging and disease[J]. Trends Cell Biol, 2014, 24 (8): 464-471. doi: 10.1016/j.tcb.2014.04.002

[40] Reustle A, Torzewski M. Role of p38 MAPK in atherosclerosis and aortic valve sclerosis[J]. Int J Mol Sci, 2018, 19 (12): 3761. doi: 10.3390/ijms19123761

[41] Goldsmith CS, Bell-Pedersen D. Diverse roles for MAPK signaling in circadian clocks[J]. Adv Genet, 2013, 84: 1-39. doi: 10.1016/B978-0-12-407703-4.00001-3

[42] Li B, Li D, Ni H, et al. The circadian clock regulator Bmal1 affects traumatic brain injury in rats through the p38 MAPK signalling pathway[J]. Brain Res Bull, 2022, 178: 17-28. doi: 10.1016/j.brainresbull.2021.11.003

[43] Duregon E, Pomatto-Watson LCDD, Bernier M, et al. Intermittent fasting: From calories to time restriction[J]. GeroScience, 2021, 43 (3): 1083-1092. doi: 10.1007/s11357-021-00335-z

[44] Naous E, Achkar A, Mitri J. Intermittent fasting and its effects on weight, glycemia, lipids, and blood pressure: A narrative review[J]. Nutrients, 2023, 15 (16): 3661. doi: 10.3390/nu15163661

[45] Jamshed H, Beyl RA, Della Manna DL, et al. Early time-restricted feeding improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans[J]. Nutrients, 2019, 11 (6): 1234. doi: 10.3390/nu11061234

[46] Pignatta S, Cortesi M, Arienti C, et al. Effects of radiotherapy and short-term starvation combination on metastatic and non-tumor cell lines[J]. DNA Repair (Amst), 2020, 95: 102949. doi: 10.1016/j.dnarep.2020.102949

[47] Kavanagh K, Bashore AC, Davis MA, et al. Early time-restricted feeding improves high-density lipoprotein amount and function in nonhuman primates, without effects on body composition[J]. Obesity (Silver Spring), 2023, 31 Suppl 1 (Suppl 1): 75-84. doi: 10.1002/oby.23564

[48] Dorighello GG, Rovani JC, Luhman CJF, et al. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice[J]. Br J Nutr, 2014, 111 (6): 979-986. doi: 10.1017/S0007114513003383

[49] Okoshi K, Cezar MDM, Polin MAM, et al. Influence of intermittent fasting on myocardial infarction-induced cardiac remodeling[J]. BMC Cardiovasc Disord, 2019, 19 (1): 126. doi: 10.1186/s12872-019-1113-4