Archives of Academic Emergency Medicine. 2019; 7 (1): e16 OR I G I N A L RE S E A RC H Effects of Supplementation and Training on Ameliorating Lipid Profiles and Protection against Coronary Artery Dis- ease; an Experimental Study Reza Vafaee1,2, Hamid Soori3, Mehdi Hedayati4, Hamid Reza Hatamabadi5∗ 1. Safety Promotion and Injury Prevention Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Safety Promotion and Injury Prevention Research Center, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Safety Promotion and Injury Prevention Research Center, Department of Emergency Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: November 2018; Accepted: December 2018; Published online: 12 February 2019 Abstract: Introduction: The use of antioxidants may reduce the harmful effects of radicals during exercise and extreme sports. The Current study aimed to investigate the effect of this supplement on the lipid profiles in exercise- induced muscle injury. Methods: In this experimental study, 64 Wistar rats were randomly divided into four groups of control, exercise, exercise+Resveratrol (REV ) and REV. After a week of adaptation, endurance and acute exercises were conducted in a motor driven treadmill, followed by using a training protocol in which running speed was gradually elevated until 19 weeks of age. Finally, the levels of cholesterol (CHO), triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and very low-density lipoproteins (VLDL) were compared between the groups. Results: There was no statistically significant difference in CHO plasma level be- tween the studied groups after acute and endurance exercises. There was a significant increase in the level of TG in the exercise group (p = 0.001) and the exercise+REV (p = 0.004) group after acute and endurance exercises. After the implementation of the endurance and acute exercises none of the studied groups had statistically sig- nificant changes in HDL plasma level. There was a significant decrease in LDL plasma levels in the exercise (p = 0.007) and the exercise+REV (p = 0.01) groups. After performing endurance protocol, VLDL plasma levels increased significantly in the exercise (p = 0.001) and the exercise+REV (p = 0.005) groups in comparison with control group. Conclusion: Based on the findings, there was no difference in the level of CHO and HDL between the training groups, REV and control groups. However, both endurance exercise and acute exercise trainings resulted in an increase in TG and VLDL levels and decrease in LDL level, compared with the control group. Keywords: Resveratrol supplementation; lipid profiles; Wistar rat; endurance and acute exercise trainings Cite this article as: Vafaee R, Soori H, Hedayati M, Hatamabadi H. Effects of Supplementation and Training on Ameliorating Lipid Profiles and Protection against Coronary Artery Disease; an Experimental Study. Arch Acad Emerg Med. 2019; 7(1): e16. 1. Introduction Cardiovascular disease will cause more than 75% of deaths worldwide by 2020, if this trend continues, about 24.4 mil- ∗Corresponding Author: Hamid Reza Hatamabadi; Emergency Department, Imam Hossein Hospital, Shahid Madani Avenue, Imam Hossein Square, Tehran, Iran. Email: hhatamabadi@yahoo.com lion people will die before 2030 (1, 2). Physical inactivity emphasizes adverse outcomes such as atherosclerosis, dia- betes, obesity, and metabolic syndrome. On the other hand, sports activities can be capable of reducing and preventing such diseases (3, 4). One of the most sensitive targets for peroxidants can be non-saturated fatty acids in biological membranes that interfere with the pathogenesis of many dis- eases. Furthermore, cellular toxicity metabolites from lipid This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem R. Vafaee et al. 2 peroxides play a significant role in the oxidation of proteins present in low-density lipoprotein (LDL). This trend is also important in the pathogenesis of atherosclerosis (5). Phys- ical activity can lead to a 1.8-fold increase in lipid peroxi- dation after 60 minutes of intense cycling exercise. On the other hand, the implementation of intense and prolonged exercise can also lead to functional impairment of immu- nity, inflammation, oxidative stress and muscle damage (6, 7). Exercise-induced oxidative stress may be neutralized with antioxidants. Antioxidants, even at very low concentrations, along with an oxidizing agent, prevent oxidation of this ox- idizing agent and are capable of delaying it (8, 9). The use of antioxidants improves the antioxidant status of the body and may reduce the harmful effects of radicals during exer- cise and extreme sports (9, 10). Resveratrol (REV ) has been introduced for the first time in the 1940s in the Cassia Quni- quangulata. It has many therapeutic aspects and has been previously used in Iran since around 6,000 years BC (11). The Chinese and Japanese used a plant called Polygonum Cus- pidatum in the year 100 BC to treat many diseases. In the 1960s, Rev was isolated from this plant (12). REV is a spe- cific polyphenol compound and its antioxidant nature is high due to the presence of two phenolic rings on both sides of the double bond; indeed, this stilbenoid is one of the most potent antioxidants found in nature (13, 14). A number of reports suggested that co-administration of REV with statins was capable of increasing the cardio-protective effect of pa- tients with cardiac arrhythmias. Chen et al. revealed the in- hibitory effect of REV on cardiac hypertrophy in 2008 (15). The supplementation of REV in prevention and treatment of cardiovascular diseases was initially investigated by control- ling LDL, which is the main cause of atherosclerosis progres- sion (16). REV protects the heart against myocardial damage following ischemia, and it has been shown that the supple- mentation of REV has improved cardiac function in hyper- tension induced in laboratory rats (17). Considering the pos- itive effect of REV on inhibiting oxidative stress and inflam- matory response from free radicals, the present study was aimed to investigate the effect of this supplement on the lipid profiles in exercise-induced muscle injury. 2. Methods 2.1. Study design and setting This experimental study was performed in Shahid Beheshti University of Medical Sciences from February 2017 to March 2018. Male Wistar rats were randomly divided into four groups: control, exercise, REV, and exercise+REV and their lipid profiles were compared after interventions. All an- imals were enrolled in the study according to approved guidelines for care and use of laboratory animals. They were given a standard commercial diet that was purchased from Pars Animal Feed Company, Iran. The protocol of the study was approved by the local ethical committee (IR.SBMU.MSP.1396.372). 2.2. Participants Sixty-four male Wistar rats (165–175 g; 6-weeks-old) were ob- tained from Razi Research Institute of Karaj, Iran, and housed into standard conditions in groups of 4 animals per cage (18”× 10”× 8”) under a 12 h light/dark cycle, at 22 ± 3◦C, with a 45% relative humidity. Overall, a total of 16 male Wistar rats per group were included in the present study. 2.3. Intervention Male Wistar rats in trained group were subjected to the fa- miliarization step for one week exercising on a rodent tread- mill for 10 minutes, three times a week, in which the run- ning speed was set to 5 to 10 m/min. Additionally, the control groups had access to the treadmill running three days during the week for 10 minutes, where exercise session was planned to be constant at a slow speed with an electrical stimu- lator. REV supplementation (10 mg/kg of REV in ethanol 2%/100 mL H2O) was began during exercise. On the other hand, those in the control group were also administered with water-containing ethanol 2% /100mL H2O as the vehicle. 2.4. Exercise protocol After a week of adaptation, the rats began performing the protocol at 8 weeks of age. The training included endurance and acute exercises, which were conducted in a motor- driven treadmill at a speed of 10 m/minute, 20 min/day for 5 days/week, followed by applying a training protocol in which running speed was gradually elevated to 30 m/min for 60 min/day until 19 weeks of age. It is noteworthy that exer- cise intensity was adjusted to 65% maximal oxygen uptake (VO2max) as described previously (18). The animals were sacrificed intra-peritoneally with 30-50 mg/kg ketamine and 3-5 mg/kg xylosin three days after the last exercise proce- dure for avoiding acute metabolic effects induced by the fi- nal run. Between 7 and 10 ml of blood samples were ob- tained at sacrifice by cardiac puncture in a heparin-treated 10-ml syringe. After that, all samples were centrifuged for 15 min at 3000×g at 4◦C, and serum samples were imme- diately stored at – 20◦C until use. Lipid profiles including cholesterol (CHO), Triglycerides (TG), low-density lipopro- teins (LDL), high-density lipoproteins (HDL), and very low- density lipoproteins (VLDL) were biochemically measured using commercially available kits according to the manufac- turer’s protocols. 2.5. Statistical Analysis The data was collected by the first author. All Data were processed and analyzed using IBM SPSS Statistics ver. 21.0. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e16 Figure 1: Comparison of plasma triglycerides changes in acute ex- ercise (a) and endurance exercise (b) groups. C = control group, T = train or exercise group, S = supplement or resveratrol, T+S = exer- cise+resveratrol. Error bar = 95% confidence interval. For statistical evaluation of the changes in all groups, we ap- plied one-way analysis of variance (ANOVA). Statistical sig- nificance was set at P<0.05. Additionally, Tukey’s test was ap- plied for post-hoc comparisons. 3. Results Tables 1 and 2 compare the changes of lipid profile between different groups after acute and endurance exercises. 3.1. CHO plasma levels There was no statistically significant difference in CHO plasma level between the studied groups after acute and en- durance exercises (Tables 1 and 2). 3.2. TG plasma levels Following the implementation of the endurance exercise pro- tocols, there was a significant increase in the level of TG in the exercise group (p = 0.001) and the exercise+REV (p = 0.004) group compared to the control group, but no significant dif- ference was found in terms of plasma TG levels between the exercise and exercise+REV groups (p = 0.450; Table 1). On the other hand, a statistically significant increase was ob- served in plasma TG levels in the exercise (p < 0.001) and exercise+REV (p = 0.002) groups compared with the control group after performing acute protocol. However, the plasma TG levels in the REV group demonstrated a significant de- crease compared to the exercise group (p < 0.001; Table 2). There was a significant difference between the TG plasma level of exercise group after acute and endurance exercises (p = 0.03, figure 1). 3.3. HDL plasma levels As shown in tables 1 and 2; after the implementation of the endurance and acute exercise none of the studied groups had statistically significant changes in HDL plasma level. Also, no statistically significant difference was revealed in the HDL plasma level between the groups undergoing endurance and acute exercises. 3.4. LDL plasma level There was a significant decrease in LDL plasma levels in ex- ercise (p = 0.007) and exercise + REV (p = 0.01) groups com- pared to control group. After performance of the acute exer- cise, plasma LDL level showed a significant decrease in the exercise group compared with the control group (p = 0.049). There was no statistically significant difference in the LDL plasma levels between endurance and acute exercise groups. 3.5. VLDL plasma levels After performing endurance protocol, VLDL plasma levels in- creased significantly in the exercise (p = 0.001) and the ex- ercise+ REV (p = 0.005) groups in comparison with control group. After implementation of the acute protocol, there was a significant increase in plasma VLDL level in the ex- ercise group (P < 0.0001) and the exercise+REV group (p = 0.002) when compared with the control group. However, VLDL plasma levels in the exercise+REV exhibited a statisti- cally significant difference compared to the exercise group (p = 0.001). Furthermore, the VLDL plasma level did not reveal a significant difference between endurance and the acute ex- ercises. 4. Discussion Based on the findings, there was no difference between the training groups, REV and control groups regarding the level of CHO and HDL. However, both endurance exercise and acute exercise trainings resulted in an increase in TG and VLDL levels and decrease in LDL level in comparison with the control group. A growing body of evidence has shown that regular exercise with moderate intensity prevents cardiovas- cular disease due to increased HDL level in the blood. Regu- lar exercise boosts the antioxidant system and prevents car- diovascular disease in the long run. Santin et al. reported that levels of CHO and LDL decreased in rats with mild exercise, but no change was found in levels of HDL and TG (19). REV exerts many effects, such as antioxidant activity, regulation of lipid and lipoprotein metabolism, inhibition of platelet ag- gregation, and vasodilation (20, 21). REV, as the activator of the enzyme AMPK, plays a role in regulating lipid metabolism and prevents the accumulation of lipid in the cells, where it has been revealed that a synthesized derivative of REV was capable of enhancing AMPK phosphorylation, and reducing This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem R. Vafaee et al. 4 Table 1: Changes in plasma levels of cholesterol (CHO), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) after endurance exercise Group CHO P TG P HDL P LDL P VLDL P C 51.61(38.35) 65(22.07) 33.5(1.64) 33.66(6.88) 13(4.41) vs. 0.96 <0.001 0.42 0.007 <0.001 T 56.37(9.5) 119.12(23.48) 36.5(2.44) 19.62(6.67) 23.82(4.69) C 51.61(38.35) 65(22.07) 33.5(1.64) 33.66(6.88) 13(4.41) vs. 0.94 0.66 0.2 0.74 0.66 S 57.71(6.62) 76.85(15.42) 37.57(5.06) 29.57(7.2) 15.37(3.08) C 51.61(38.35) 65(22.07) 33.5(1.64) 33.66(6.88) 13(4.41) vs. 0.97 0.004 0.1 0.01 0.005 T+S 55.85(10.62) 104.57(10.34) 38.28(4.07) 20.28(8.11) 20.9(2.08) T 56.37(9.5) 119.12(23.48) 36.5(2.44) 19.62(6.67) 23.82(4.69) vs. 0.99 0.001 0.93 0.06 0.001 S 57.71(6.62) 76.85(15.42) 37.57(5.06) 29.57(7.2) 15.37(3.08) T 56.37(9.5) 119.12(23.48) 36.5(2.44) 19.62(6.67) 23.82(4.69) vs. 1.0 0.45 0.77 0.99 0.44 T+S 55.85(10.62) 104.57(10.34) 38.28(4.07) 20.28(8.11) 20.9(2.08) S 57.71(6.62) 76.85(15.42) 37.57(5.06) 29.57(7.2) 15.37(3.08) vs. 0.99 0.04 0.98 0.1 0.04 T+S 55.85(10.62) 104.57(10.34) 38.28(4.07) 20.28(8.11) 20.9(2.08) C = control group, T = train or exercise group, S = supplement or resveratrol, T+S = exercise + resveratrol. Table 2: Changes in plasma levels of cholesterol (CHO), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) after acute exercise Group CHO P TG P HDL P LDL P VLDL P C 40.71(8.51) 67.57(14.5) 35.14(3.71) 34.71(10.78) 13.51(2.9) vs. 0.32 <0.001 0.85 0.04 <0.001 T 52(12.4) 148.25(7.41) 37.5(3.87) 15.5(7.54) 29.65(1.48) C 40.71(8.51) 67.57(14.5) 35.14(3.71) 34.71(10.78) 13.51(2.9) vs. 0.08 0.68 0.53 0.67 0.68 S 54.25(12.2) 76.37(18.85) 38.5(5.04) 28.25(14.12) 15.25(3.72) C 40.71(8.51) 67.57(14.5) 35.14(3.71) 34.71(10.78) 13.51(2.9) vs. 0.57 0.002 0.7 0.28 0.002 T+S 48.16(7.8) 102.83(14.64) 38(5.83) 23.5(7.25) 20.56(2.92) T 52(12.4) 148.25(7.41) 37.5(3.87) 15.5(7.54) 29.65(1.48) vs. 0.98 <0.001 0.98 0.25 0.001 S 54.25(12.2) 76.37(18.85) 38.5(5.04) 28.25(14.12) 15.25(3.72) T 52(12.4) 148.25(7.41) 37.5(3.87) 15.5(7.54) 29.65(1.48) vs. 0.93 0.001 0.99 0.67 0.001 T+S 48.16(7.8) 102.83(14.64) 38(5.83) 23.5(7.25) 20.56(2.92) S 54.25(12.2) 76.37(18.85) 38.5(5.04) 28.25(14.12) 15.25(3.72) vs. 0.7 0.02 0.99 0.85 0.02 T+S 48.16(7.8) 102.83(14.64) 38(5.83) 23.5(7.25) 20.56(2.92) C = control group, T = train or exercise group, S = supplement or resveratrol, T+S = exercise + resveratrol. hepatic TG accumulation, showing a significant therapeutic effect on fatty liver disease (22). In the study by Kitada et al., oral administration of Risoratrol to diabetic mouse mod- els improved their lipid profiles (23). In other words, the aforementioned study indicated that REV could be an effec- tive supplement for improving renal injury and was capable of increasing mitochondrial biogenesis with Mn-SOD dys- function in diabetic mouse models by improving oxidative stress, as well as normalization of the Mn-SOD function and glucose-lipid metabolism, suggesting an anti-oxidative ac- tivity for REV by affecting AMPK/SIRT1-independent path- way(23). Castro et al. found that REV could play a signif- icant role in preventing LDL deposition in the aortic artery endothelium and accelerating its recovery, showing a preven- tive effect in development of atherosclerotic lesions (24). The findings of the present study are consistent with the findings of Kitada et al. (23) and Zhu et al. (25), in which this combi- nation was involved in improving lipid profiles. Our results This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2019; 7 (1): e16 also exhibited a significant decrease in TG and VLDL levels in the exercise group+REV compared to the training group. However, some believe that improvement of coronary heart diseases by REV is not due to its antioxidant property against lipids and changing lipoprotein profile (26). Zhu et al. also demonstrated both antioxidant and anti-hyper-lipidemic ef- fects for REV. They showed that administration of REV in hy- perlipidemia rats has a significant effect on lipid profiles and plays a role in decreasing lipid profile (TG and CHO levels) by decreasing hepatic thiobarbituric acid reactive substances via inhibition of the oxidation of LDL (25). On the other hand, Tome-Carneiro et al. reported that a grape extract supple- ment containing REV led to a decrease in the level of oxidized LDL and apolipoprotein-B in patients at high risk of a cardio- vascular disease. This supplement was capable of decreas- ing atherogenic markers and was involved in cardioprotec- tion (21). However, in the current study, the supplementa- tion of REV did not change the level of LDL. This finding is incompatible with Tome-Carneiro et al. (21). Overall, since REV reduces the level of TG, it seems that REV may show a protective effect against lipid peroxidation in athletes by im- proving the lipid profile and reducing peroxidation of lipids. However, these effects can be affected by several other factors such as type and duration of exercise, the type of model ex- amined, the amount and timing of resveratrol supplementa- tion and other factors. Therefore, further studies are required to clarify the effect of this supplement on lipid profiles during endurance and acute exercise. 5. Conclusion Based on the findings, there was no difference in the level of CHO and HDL between the training groups, REV and control groups. However, both endurance exercise and acute exer- cise trainings resulted in an increase in TG and VLDL levels and decrease in LDL level, compared with the control group. 6. Appendix 6.1. Acknowledgements Not Applicable. 6.2. Authors’ contribution All the authors met the criteria of authorship based on the recommendations of the international committee of medical journal editors. Authors ORCIDs Reza Vafaee: 0000-0003-0677-4755 Hamid Soori: 0000-0002-3775-1831 Mehdi Hedayati: 0000-0001-5816-775X Hamid Reza Hatamabadi: 0000-0002-9085-8806 6.3. Funding/Support This study was supported technically and financially by Shahid Beheshti University of Medical Sciences. 6.4. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Appendix References