Document Type : Review Article

Author

Research Working Group, General Directorate of Education, Scientific Association of Physical Education Teachers, Kermanshah, Iran.

10.22089/jehs.2024.16826.1086

Abstract

The prevalence of atherosclerotic cardiovascular disease (ASCVD) and its complications have increased substantially in recent decades. ASCVD is associated with cardiovascular diseases and is an indirect cause of a high death rate in the general population. Salusin-α and salusin-β are two endogenous bioactive peptides that could be candidate biomarkers for ASCVD. Salusin-α protects against the development of ASCVD, and a decrease in its levels is associated with ASCVD. While salusin-β plays a role in the development and/or maintenance of ASCVD and the exaggerated expression in atherosclerotic lesions. Changes in people's lifestyles, especially sedentary behavior, and a lack of exercise, are recognized as critical risk factors for cardiovascular disease. Hence, physical exercise (PE) recently had been identified as effective strategies for lowering cardiovascular disease risk. In this review, we summarize the current knowledge on the effects of PE on ASCVD through modulation of the expression of endogenous bioactive peptides with pro-and-anti-atherogenic properties.

  1. Singh, M., & Bedi, U. S. (2013). Is atherosclerosis regression a realistic goal of statin therapy and what does that mean?. Current Atherosclerosis Reports, 15(1), 294. https://doi.org/10.1007/s11883-012-0294-4.
  2. Safiri, S., Karamzad, N., Singh, K., Carson-Chahhoud, K., Adams, C., Nejadghaderi, S. A., Almasi-Hashiani, A., Sullman, M. J. M., Mansournia, M. A., Bragazzi, N. L., Kaufman, J. S., Collins, G. S., & Kolahi, A. A. (2022). Burden of ischemic heart disease and its attributable risk factors in 204 countries and territories, 1990-2019. European Journal of Preventive Cardiology, 29(2), 420–431. https://doi.org/10.1093/eurjpc/zwab213.
  3. Gibson, M. S., Domingues, N., & Vieira, O. V. (2018). Lipid and Non-lipid Factors Affecting Macrophage Dysfunction and Inflammation in Atherosclerosis. Frontiers in Physiology, 9, 654. https://doi.org/10.3389/fphys.2018.00654.
  4. Shichiri, M., Ishimaru, S., Ota, T., Nishikawa, T., Isogai, T., & Hirata, Y. (2003). Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities. Nature Medicine, 9(9), 1166–1172. https://doi.org/10.1038/nm913.
  5. Qian, K., Feng, L., Sun, Y., Xiong, B., Ding, Y., Han, P., Chen, H., Chen, X., Du, L., & Wang, Y. (2018). Overexpression of Salusin-α Inhibits Vascular Intimal Hyperplasia in an Atherosclerotic Rabbit Model. BioMed Research International, 8973986. https://doi.org/10.1155/2018/8973986.
  6. Sipahi, S., Genc, A. B., Acikgoz, S. B., Yildirim, M., Aksoy, Y. E., Vatan, M. B., Dheir, H., & Altındis, M. (2019). Relationship of salusin-alpha and salusin-beta levels with atherosclerosis in patients undergoing haemodialysis. Singapore Medical Journal, 60(4), 210–215. https://doi.org/10.11622/smedj.2018123.
  7. Watanabe, T., Suguro, T., Sato, K., Koyama, T., Nagashima, M., Kodate, S., Hirano, T., Adachi, M., Shichiri, M., & Miyazaki, A. (2008). Serum salusin-alpha levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients. Hypertension research: Official Journal of Japanese Society of Hypertension, 31(3), 463–468. https://doi.org/10.1291/hypres.31.463.
  8. Wang, Y., Wang, S., Zhang, J., Zhang, M., Zhang, H., Gong, G., Luo, M., Wang, T., & Mao, X. (2020). Salusin-β is superior to salusin-α as a marker for evaluating coronary atherosclerosis. The Journal of International Medical Research, 48(2), 300060520903868. https://doi.org/10.1177/0300060520903868.
  9. Watanabe, T., Sato, K., Itoh, F., Iso, Y., Nagashima, M., Hirano, T., & Shichiri, M. (2011). The roles of salusins in atherosclerosis and related cardiovascular diseases. Journal of the American Society of Hypertension : JASH, 5(5), 359–365. https://doi.org/10.1016/j.jash.2011.06.003.
  10. Szostak, J., & Laurant, P. (2011). The forgotten face of regular physical exercise: a 'natural' anti-atherogenic activity. Clinical science (London, England: 1979), 121(3), 91–106. https://doi.org/10.1042/CS20100520.
  11. Sawyer, B. J., Tucker, W. J., Bhammar, D. M., Ryder, J. R., Sweazea, K. L., & Gaesser, G. A. (2016). Effects of high-intensity interval training and moderate-intensity continuous training on endothelial function and cardiometabolic risk markers in obese adults. Journal of Applied Physiology (Bethesda, Md.: 1985), 121(1), 279–288. https://doi.org/10.1152/japplphysiol.00024.2016.
  12. Vella, C. A., Taylor, K., & Drummer, D. (2017). High-intensity interval and moderate-intensity continuous training elicit similar enjoyment and adherence levels in overweight and obese adults. European Journal of Sport Science, 17(9), 1203–1211. https://doi.org/10.1080/17461391.2017.1359679.
  13. Paahoo, A., Tadibi, V., Behpoor, N. (2020). Effect of Two Chronic Exercise Protocols on Pre-Atherosclerotic and Anti-Atherosclerotic Biomarkers Levels in Obese and Overweight Children. Iran J Pediatr, 30(2), e99760. https://doi.org/10.5812/ijp.99760.
  14. Paahoo, A., Tadibi, V., & Behpoor, N. (2021). Effectiveness of Continuous Aerobic Versus High-Intensity Interval Training on Atherosclerotic and Inflammatory Markers in Boys With Overweight/Obesity. Pediatric Exercise Science, 33(3), 132–138. https://doi.org/10.1123/pes.2020-0138.
  15. Nagashima, M., Watanabe, T., Shiraishi, Y., Morita, R., Terasaki, M., Arita, S., Hongo, S., Sato, K., Shichiri, M., Miyazaki, A., & Hirano, T. (2010). Chronic infusion of salusin-alpha and -beta exerts opposite effects on atherosclerotic lesion development in apolipoprotein E-deficient mice. Atherosclerosis, 212(1), 70–77. https://doi.org/10.1016/j.atherosclerosis.2010.04.027.
  16. Bruno, G., Cencetti, F., Pertici, I., Japtok, L., Bernacchioni, C., Donati, C., & Bruni, P. (2015). CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P3 signaling axis: Implications in the action mechanism of TGFβ. Biochimica et biophysica acta, 1851(2), 194–202. https://doi.org/10.1016/j.bbalip.2014.11.011.
  17. Watanabe, T., Nishio, K., Kanome, T., Matsuyama, T. A., Koba, S., Sakai, T., Sato, K., Hongo, S., Nose, K., Ota, H., Kobayashi, Y., Katagiri, T., Shichiri, M., & Miyazaki, A. (2008). Impact of salusin-alpha and -beta on human macrophage foam cell formation and coronary atherosclerosis. Circulation, 117(5), 638–648. https://doi.org/10.1161/CIRCULATIONAHA.107.712539.
  18. Ozelius, L. J., Page, C. E., Klein, C., Hewett, J. W., Mineta, M., Leung, J., Shalish, C., Bressman, S. B., de Leon, D., Brin, M. F., Fahn, S., Corey, D. P., & Breakefield, X. O. (1999). The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. Genomics, 62(3), 377–384. https://doi.org/10.1006/geno.1999.6039.
  19. Izumiyama, H., Tanaka, H., Egi, K., Sunamori, M., Hirata, Y., & Shichiri, M. (2005). Synthetic salusins as cardiac depressors in rat. Hypertension (Dallas, Tex. : 1979), 45(3), 419–425. https://doi.org/10.1161/01.HYP.0000156496.15668.62.
  20. Yu, F., Zhao, J., Yang, J., Gen, B., Wang, S., Feng, X., Tang, C., & Chang, L. (2004). Salusins promote cardiomyocyte growth but does not affect cardiac function in rats. Regulatory Peptides, 122(3), 191–197. https://doi.org/10.1016/j.regpep.2004.06.013.
  21. Sato, K., Sato, T., Susumu, T., Koyama, T., & Shichiri, M. (2009). Presence of immunoreactive salusin-beta in human plasma and urine. Regulatory Peptides, 158(1-3), 63–67. https://doi.org/10.1016/j.regpep.2009.07.017.
  22. Ponticos, M., & Smith, B. D. (2014). Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. Journal of Biomedical Research, 28(1), 25–39. https://doi.org/10.7555/JBR.27.20130064.
  23. Xiao-Hong, Y., Li, L., Yan-Xia, P., Hong, L., Wei-Fang, R., Yan, L., An-Jing, R., Chao-Shu, T., & Wen-Jun, Y. (2006). Salusins protect neonatal rat cardiomyocytes from serum deprivation-induced cell death through upregulation of GRP78. Journal of CardiovascularP, 48(2), 41–46. https://doi.org/10.1097/01.fjc.0000242059.89430.ac.
  24. Saito, T., Dayanithi, G., Saito, J., Onaka, T., Urabe, T., Watanabe, T. X., Hashimoto, H., Yokoyama, T., Fujihara, H., Yokota, A., Nishizawa, S., Hirata, Y., & Ueta, Y. (2008). Chronic osmotic stimuli increase salusin-beta-like immunoreactivity in the rat hypothalamo-neurohypophyseal system: possible involvement of salusin-beta on [Ca2+]i increase and neurohypophyseal hormone release from the axon terminals. Journal of Neuroendocrinology, 20(2), 207–219. https://doi.org/10.1111/j.1365-2826.2007.01632.x.
  25. Aydin, S., & Aydin, S. (2014). Salusin-alpha and -beta expression in heart and aorta with and without metabolic syndrome. Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission, 89(2), 98–103. https://doi.org/10.3109/10520295.2013.821167.
  26. Çakır, M., Sabah-Özcan, S., & Saçmacı, H. (2019). Increased level of plasma salusin-α and salusin-β in patients with multiple sclerosis. Multiple Sclerosis and Related Disorders, 30, 76–80. https://doi.org/10.1016/j.msard.2019.02.003.
  27. Koya, T., Miyazaki, T., Watanabe, T., Shichiri, M., Atsumi, T., Kim-Kaneyama, J. R., & Miyazaki, A. (2012). Salusin-β accelerates inflammatory responses in vascular endothelial cells via NF-κB signaling in LDL receptor-deficient mice in vivo and HUVECs in vitro. American journal of physiology. Heart and Circulatory Physiology, 303(1), H96–H105. https://doi.org/10.1152/ajpheart.00009.2012.
  28. Zhou, C. H., Liu, L., Liu, L., Zhang, M. X., Guo, H., Pan, J., Yin, X. X., Ma, T. F., & Wu, Y. Q. (2014). Salusin-β not salusin-α promotes vascular inflammation in ApoE-deficient mice via the I-κBα/NF-κB pathway. PloS one, 9(3), e91468. https://doi.org/10.1371/journal.pone.0091468.
  29. Kimoto, S., Sato, K., Watanabe, T., Suguro, T., Koyama, T., & Shichiri, M. (2010). Serum levels and urinary excretion of salusin-alpha in renal insufficiency. Regulatory Peptides, 162(1-3), 129–132. https://doi.org/10.1016/j.regpep.2010.03.009.
  30. Sato, K., Koyama, T., Tateno, T., Hirata, Y., & Shichiri, M. (2006). Presence of immunoreactive salusin-alpha in human serum and urine. Peptides, 27(11), 2561–2566. https://doi.org/10.1016/j.peptides.2006.06.005.
  31. Kołakowska, U., Kuroczycka-Saniutycz, E., Wasilewska, A., & Olański, W. (2015). Is the serum level of salusin-β associated with hypertension and atherosclerosis in the pediatric population?. Pediatric Nephrology (Berlin, Germany), 30(3), 523–531. https://doi.org/10.1007/s00467-014-2960-y.
  32. Du, S. L., Wang, W. J., Wan, J., Wang, Y. G., Wang, Z. K., & Zhang, Z. (2013). Serum salusin-α levels are inversely correlated with the presence and severity of coronary artery disease. Scandinavian Journal of Clinical and Laboratory Investigation, 73(4), 339–343. https://doi.org/10.3109/00365513.2013.783227.
  33. Liu, J., Ren, Y. G., Zhang, L. H., Tong, Y. W., & Kang, L. (2015). Serum salusin-β levels are associated with the presence and severity of coronary artery disease. Journal of Investigative Medicine The Official Publication of the American Federation for Clinical Research, 63(4), 632–635. https://doi.org/10.1097/JIM.0000000000000184.
  34. Li, H. B., Qin, D. N., Suo, Y. P., Guo, J., Su, Q., Miao, Y. W., Sun, W. Y., Yi, Q. Y., Cui, W., Cheng, K., Zhu, G. Q., & Kang, Y. M. (2015). Blockade of Salusin-β in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats. Journal of Cardiovascular Pharmacology, 66(4), 323–331. https://doi.org/10.1097/FJC.0000000000000284.
  35. Awad, A. Ali, H. Al-Rufaie, M. (2020). Assessment of serum levels of salusin α and salusin β in cardiovascular disease patients undergoing transcatheter therapy. Indian J Med Forensic Med Toxicol, 14(2), 303–308. doi:10.37506/ijfmt.v14i2.2807.
  36. Yildirim, A., & Kucukosmanoglu, M. (2021). Relationship between Serum Salusin Beta Levels and Coronary Artery Ectasia. Acta Cardiologica Sinica, 37(2), 130–137. https://doi.org/10.6515/ACS.202103_37(2).20200910A.
  37. Arkan, A., Atukeren, P., Ikitimur, B., Simsek, G., Koksal, S., Gelisgen, R., Ongen, Z., & Uzun, H. (2021). The importance of circulating levels of salusin-α, salusin-β, and heregulin-β1 in atherosclerotic coronary arterial disease. Clinical Biochemistry, 87, 19–25. https://doi.org/10.1016/j.clinbiochem.2020.10.003.
  38. Akyüz, A., Aydın, F., Alpsoy, Ş., Ozkaramanli Gur, D., & Guzel, S. (2019). Relationship of serum salusin beta levels with coronary slow flow. Anatolian Journal of Cardiology, 22(4), 177–184. https://doi.org/10.14744/AnatolJCardiol.2019.43247.
  39. Sato, K., Watanabe, R., Itoh, F., Shichiri, M., & Watanabe, T. (2013). Salusins: potential use as a biomarker for atherosclerotic cardiovascular diseases. International Journal of Hypertension, 2013, 965140. https://doi.org/10.1155/2013/965140.
  40. Piko, N., Bevc, S., Hojs, R., & Ekart, R. (2023). Atherosclerosis and Epigenetic Modifications in Chronic Kidney Disease. Nephron, 147(11), 655–659. https://doi.org/10.1159/000531292.
  41. Sarwar, N., Danesh, J., Eiriksdottir, G., Sigurdsson, G., Wareham, N., Bingham, S., Boekholdt, S. M., Khaw, K. T., & Gudnason, V. (2007). Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation, 115(4), 450–458. https://doi.org/10.1161/CIRCULATIONAHA.106.637793.
  42. Celik, Ö., Yılmaz, E., Celik, N., Minareci, Y., Turkcuoglu, I., Simsek, Y., Celik, E., Karaer, A., & Aydin, S. (2013). Salusins, newly identified regulators of hemodynamics and mitogenesis, increase in polycystic ovarian syndrome. Gynecological endocrinology: the official journal of the International Society of Gynecological Endocrinology, 29(1), 83–86. https://doi.org/10.3109/09513590.2012.706667.
  43. Grzegorzewska, A. E., Niepolski, L., Sikora, J., Janków, M., Jagodziński, P. P., & Sowińska, A. (2014). Effect of lifestyle changes and atorvastatin administration on dyslipidemia in hemodialysis patients: a prospective study. Polskie Archiwum Medycyny Wewnetrznej, 124(9), 443–451. https://doi.org/10.20452/pamw.2401.
  44. Tsimikas, S., Miyanohara, A., Hartvigsen, K., Merki, E., Shaw, P. X., Chou, M. Y., Pattison, J., Torzewski, M., Sollors, J., Friedmann, T., Lai, N. C., Hammond, H. K., Getz, G. S., Reardon, C. A., Li, A. C., Banka, C. L., & Witztum, J. L. (2011). Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression. Journal of the American College of Cardiology, 58(16), 1715–1727. https://doi.org/10.1016/j.jacc.2011.07.017.
  45. Hai, Z., & Zuo, W. (2016). Aberrant DNA methylation in the pathogenesis of atherosclerosis. Clinica Chimica Acta; International Journal of Clinical Chemistry, 456, 69–74. https://doi.org/10.1016/j.cca.2016.02.026.
  46. Sato, K., Fujimoto, K., Koyama, T., & Shichiri, M. (2010). Release of salusin-beta from human monocytes/macrophages. Regulatory Peptides, 162(1-3), 68–72. https://doi.org/10.1016/j.regpep.2010.02.010.
  47. Nakayama, C., Shichiri, M., Sato, K., & Hirata, Y. (2009). Expression of prosalusin in human neuroblastoma cells. Peptides, 30(7), 1362–1367. https://doi.org/10.1016/j.peptides.2009.03.021.
  48. Matei, D., Buculei, I., Luca, C., Corciova, C. P., Andritoi, D., Fuior, R., Iordan, D. A., & Onu, I. (2022). Impact of Non-Pharmacological Interventions on the Mechanisms of Atherosclerosis. International Journal of Molecular Sciences, 23(16), 9097. https://doi.org/10.3390/ijms23169097.
  49. Tucker, W. J., Fegers-Wustrow, I., Halle, M., Haykowsky, M. J., Chung, E. H., & Kovacic, J. C. (2022). Exercise for Primary and Secondary Prevention of Cardiovascular Disease: JACC Focus Seminar 1/4. Journal of the American College of Cardiology, 80(11), 1091–1106. https://doi.org/10.1016/j.jacc.2022.07.004.
  50. Price, K. J., Gordon, B. A., Bird, S. R., & Benson, A. C. (2016). A review of guidelines for cardiac rehabilitation exercise programmes: Is there an international consensus?. European Journal of Preventive Cardiology, 23(16), 1715–1733. https://doi.org/10.1177/2047487316657669.
  51. Nystoriak, M. A., & Bhatnagar, A. (2018). Cardiovascular Effects and Benefits of Exercise. Frontiers in Cardiovascular Medicine, 5, 135. https://doi.org/10.3389/fcvm.2018.00135.
  52. Myers J. (2003). Cardiology patient pages. Exercise and cardiovascular health. Circulation, 107(1), e2–e5. https://doi.org/10.1161/01.cir.0000048890.59383.8d.
  53. Daniela, M., Catalina, L., Ilie, O., Paula, M., Daniel-Andrei, I., & Ioana, B. (2022). Effects of Exercise Training on the Autonomic Nervous System with a Focus on Anti-Inflammatory and Antioxidants Effects. Antioxidants (Basel, Switzerland), 11(2), 350. https://doi.org/10.3390/antiox11020350.
  54. Goh, J., Goh, K. P., & Abbasi, A. (2016). Exercise and Adipose Tissue Macrophages: New Frontiers in Obesity Research?. Frontiers in Endocrinology, 7, 65. https://doi.org/10.3389/fendo.2016.00065.
  55. Kokkinos, P., & Myers, J. (2010). Exercise and physical activity: clinical outcomes and applications. Circulation, 122(16), 1637–1648. https://doi.org/10.1161/CIRCULATIONAHA.110.948349.
  56. Haskell, W. L., Lee, I. M., Pate, R. R., Powell, K. E., Blair, S. N., Franklin, B. A., Macera, C. A., Heath, G. W., Thompson, P. D., Bauman, A., American College of Sports Medicine, & American Heart Association (2007). Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation, 116(9), 1081–1093. https://doi.org/10.1161/CIRCULATIONAHA.107.185649.
  57. Nazari, M., Minasian, V., & Hovsepian, S. (2020). Effects of Two Types of Moderate- and High-Intensity Interval Training on Serum Salusin-α and Salusin-β Levels and Lipid Profile in Women with Overweight/Obesity. Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, 13, 1385–1390. https://doi.org/10.2147/DMSO.S248476.
  58. Aengevaeren, V. L., Mosterd, A., Sharma, S., Prakken, N. H. J., Möhlenkamp, S., Thompson, P. D., Velthuis, B. K., & Eijsvogels, T. M. H. (2020). Exercise and Coronary Atherosclerosis: Observations, Explanations, Relevance, and Clinical Management. Circulation, 141(16), 1338–1350. https://doi.org/10.1161/CIRCULATIONAHA.119.044467.
  59. DeFina, L. F., Radford, N. B., Barlow, C. E., Willis, B. L., Leonard, D., Haskell, W. L., Farrell, S. W., Pavlovic, A., Abel, K., Berry, J. D., Khera, A., & Levine, B. D. (2019). Association of All-Cause and Cardiovascular Mortality With High Levels of Physical Activity and Concurrent Coronary Artery Calcification. JAMA Cardiology, 4(2), 174–181. https://doi.org/10.1001/jamacardio.2018.4628.
  60. Aengevaeren, V. L., Mosterd, A., Bakker, E. A., Braber, T. L., Nathoe, H. M., Sharma, S., Thompson, P. D., Velthuis, B. K., & Eijsvogels, T. M. H. (2023). Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study. Circulation, 147(13), 993–1003. https://doi.org/10.1161/CIRCULATIONAHA.122.061173.
  61. Bahram, M. E., Afroundeh, R., Pourvaghar, M. J., Seify Skishahr, F., Katebi, L., Isik, O. (2023). The Effect of Combined Exercises and Consumption of Mulberry Leaf Extract on Serum Inflammatory Markers Level in Elderly Type 2 Diabetes Mellitus Men. IJDO, 15(3), 129-138. doi: 10.18502/ijdo.v15i3.13733.
  62. Bartlett, J. D., Close, G. L., MacLaren, D. P., Gregson, W., Drust, B., & Morton, J. P. (2011). High-intensity interval running is perceived to be more enjoyable than moderate-intensity continuous exercise: implications for exercise adherence. Journal of Sports Sciences, 29(6), 547–553. https://doi.org/10.1080/02640414.2010.545427.