1- Department of Exercise Physiology, Vap.C, Islamic Azad University, Varamin Iran , namenifarah@gmail.com
2- Department of. Exercise Physiology, SR.C, Islamic Azad University, Tehran Iran
2- Department of. Exercise Physiology, SR.C, Islamic Azad University, Tehran Iran
Abstract: (132 Views)
Background: Adaptation to hypoxia can improve cardiac function and reduce cardiac complications of diabetes. This study aimed to determine the effect of HIIT on the expression of VEGF-A and HIF-1α in the hearts of diabetic rats.
Methods: Male Wistar rats (weighing 200–250 g and eight weeks old) were used in this study. Rats in the training group warmed up for 5 minutes, then performed a HIIT swimming protocol (14 repetitions of 20 seconds with 10 seconds of rest; eight weeks, three sessions per week). An external load equivalent to 7% of body weight was attached to the base of the tail in the first week and gradually increased by 1% in the following weeks (eighth week: load equivalent to 14% of body weight). Twenty-two rats were made diabetic by subcutaneous injection of streptozotocin. Seven days after injection, rats with blood sugar levels above 300 mg/dL were selected as diabetic samples. Eleven rats were placed in the healthy control group. After eight weeks, the rats were anesthetized and their hearts were removed for sampling. Gene expression was examined using real-time PCR. Data are presented as mean ± standard deviation; one-way ANOVA and Tukey's post hoc test were used.
Results: VEGF-A mRNA expression in the HIIT group increased by 60% compared to the diabetic group (p < 0.06). In the diabetic group, VEGF-A mRNA expression showed a 47% decrease compared to the control group (p < 0.001). HIF-1α mRNA expression in the HIIT group increased by about 27% compared to the diabetic group (p < 0.001). HIF-1α mRNA expression in the diabetic group decreased by about 25% compared to the control group (p < 0.001).
Conclusion: Diabetes impairs the expression of HIF-1α and VEGF-A, and HIIT increases the expression of these genes in heart tissue.
Methods: Male Wistar rats (weighing 200–250 g and eight weeks old) were used in this study. Rats in the training group warmed up for 5 minutes, then performed a HIIT swimming protocol (14 repetitions of 20 seconds with 10 seconds of rest; eight weeks, three sessions per week). An external load equivalent to 7% of body weight was attached to the base of the tail in the first week and gradually increased by 1% in the following weeks (eighth week: load equivalent to 14% of body weight). Twenty-two rats were made diabetic by subcutaneous injection of streptozotocin. Seven days after injection, rats with blood sugar levels above 300 mg/dL were selected as diabetic samples. Eleven rats were placed in the healthy control group. After eight weeks, the rats were anesthetized and their hearts were removed for sampling. Gene expression was examined using real-time PCR. Data are presented as mean ± standard deviation; one-way ANOVA and Tukey's post hoc test were used.
Results: VEGF-A mRNA expression in the HIIT group increased by 60% compared to the diabetic group (p < 0.06). In the diabetic group, VEGF-A mRNA expression showed a 47% decrease compared to the control group (p < 0.001). HIF-1α mRNA expression in the HIIT group increased by about 27% compared to the diabetic group (p < 0.001). HIF-1α mRNA expression in the diabetic group decreased by about 25% compared to the control group (p < 0.001).
Conclusion: Diabetes impairs the expression of HIF-1α and VEGF-A, and HIIT increases the expression of these genes in heart tissue.
Keywords: VEGF-A (Vascular Endothelial Growth Factor A), HIF1-α, High-Intensity Interval Training, diabetes
References
1. Zheng S, Ni J, Li Y, Lu M, Yao Y, Guo H, et al. 2-Methoxyestradiol synergizes with Erlotinib to suppress hepatocellular carcinoma by disrupting the PLAGL2-EGFR-HIF-1/2α signaling loop. Pharmacol Res. 2021;169:105685. [View at Publisher] [DOI] [PMID] [Google Scholar]
2. Batrakoulis A, Jamurtas AZ, Fatouros IG. High-Intensity Interval Training in Metabolic Diseases: Physiological Adaptations. ACSMs Health Fit J. 2021;25(5):54-9. [View at Publisher] [DOI] [Google Scholar]
3. Syeda UA, Battillo D, Visaria A, Malin SK. The importance of exercise for glycemic control in type 2 diabetes. Am J Med Open. 2023;9:100031. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Bayat M, Alaee M, Akbari A, Sadegh M, Latifi SA, Parastesh M, et al. A comparative study of the antidiabetic effect of two training protocols in streptozotocin-nicotinamide diabetic rats. Horm Mol Biol Clin Investig. 2020;41(2). [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Yang Ch, Zhong ZF, Wang Sh-P, Vong Ch-T, Yu B, Wang Y-T. HIF-1: structure, biology and natural modulators. Chin J Nat Med. 2021;19(7):521-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Drozdovska S, Zanou N, Lavier J, Mazzolai L, Millet GP, Pellegrin M. Moderate Effects of Hypoxic Training at Low and Supramaximal Intensities on Skeletal Muscle Metabolic Gene Expression in Mice. Metabolites. 2023;13(10):1103. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Villamil-Parra W, Cristancho-Mejía É, Ramon Torrella J, Mancera-Soto EM. Effects of a physical exercise program on HIF-1α in people with Chronic Obstructive Pulmonary Disease living at high altitude: study protocol for a clinical trial. Trials. 2023;24(1):698. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M,et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 2021;21(1):62. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. DA Silva BVC, Branco DBT, Ide BN, Marocolo M, DE Souza HLR, Arriel RA, et al. Comparison of High-Volume and High-Intensity Upper Body Resistance Training on Acute Neuromuscular Performance and Ratings of Perceived Exertion. Int J Exerc Sci. 2020;13(1):723-3. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Zokaei A, Ghahramani M, Bolouri G, Nassiri Avanaki M. Comparison of Continuous and Periodic Exercise on Serum Nitric Oxide Level and Vascular Endothelial Growth Factor in Old Rats. Mljgoums. 2023;17(2):20-25. [View at Publisher] [DOI] [Google Scholar]
11. Ghahramani M, Razavi Majd Z. The Effect of Physical Activity on VEGF and HIF-1 Signaling. J Clin Res Paramed Sci. 2020;9(2):e98493. [View at Publisher] [DOI] [Google Scholar]
12. Luo Z, Tian M, Yang G, Tan Q, Chen Y, Li G, et al. Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther. 2022;7(1):218. [View at Publisher] [DOI] [PMID] [Google Scholar]
13. Amirazodi M, Mehrabi A, Rajizadeh MA, Bejeshk MA, Esmaeilpour K, Daryanoosh F, et al. The effects of combined resveratrol and high intensity interval training on the hippocampus in aged male rats: An investigation into some signaling pathways related to mitochondria. Iran J Basic Med Sci. 2022;25(2):254-62. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Su Z, Chen L, Lu M, Li J, Qiu L, Shi L. Peripheral blood HIF-1α levels: a study on their predictive ability for early-stage diabetic retinopathy. Endocr Connect. 2025;14(5):e250004. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Cerychova R, Pavlinkova G. HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart. Front Endocrinol (Lausanne). 2018;9:460. [View at Publisher] [DOI] [PMID] [Google Scholar]
16. Thangarajah H, Vial IN, Grogan RH, Yao D, Shi Y, Januszyk M, et al. HIF-1alpha dysfunction in diabetes. Cell Cycle. 2010;9(1):75-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
17. Soltani R, Kordi MR, Gaeini AA, Nuri R. The effects of 8 weeks aerobic training on HIF-1α, miR-21 and VEGF gene expression in female Balb/c with breast cancer. Yafte. 2019;21(1):63-74. [View at Publisher] [Google Scholar]
18. De Carvalho CD, Valentim RR, Navegantes LC, Papoti M. Comparison between low, moderate, and high intensity aerobic training with equalized loads on biomarkers and performance in rats. Sci Rep. 2022;12(1):18047 [View at Publisher] [DOI] [PMID] [Google Scholar]
19. Furrer R, Handschin C. Molecular aspects of the exercise response and training adaptation in skeletal muscle. Free Radic Biol Med. 2024;223:53-68. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. Zeng Y, Tao Y, Du G, Huang T, Chen S, Fan L, et al. Advances in the mechanisms of HIF-1α-enhanced tumor glycolysis and its relation to dedifferentiation. Prog Biophys Mol Biol. 2025:197:1-10 [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Song W, Liang Q, Cai M, Tian Z. HIF-1α-induced up-regulation of microRNA-126 contributes to the effectiveness of exercise training on myocardial angiogenesis in myocardial infarction rats. J Cell Mol Med. 2020;24(22):12970-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
22. Kirsch M, Iliou M-C, Vitiello D. Hemodynamic Response to Exercise Training in Heart Failure With Reduced Ejection Fraction Patients. Cardiol Res. 2024;15(1):18-28. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Lucchesi M, Di Marsico L, Guidotti L, Lulli M, Filippi L, Marracci S, Dal Monte M. Hypoxia-Dependent Upregulation of VEGF Relies on β3-Adrenoceptor Signaling in Human Retinal Endothelial and Müller Cells. Int J Mol Sci. 2025;26(9):4043. [View at Publisher] [DOI] [PMID] [Google Scholar]
24. Kheradmand S, Asad MR, Mir Javadi R, Kheradmand N, Fashi M. Influence of Exercise Intensity on the Expression of Angiogenesis-Related Genes in the Hearts of Male Rats. J Basic Res Med Sci. 2023;10(4):43-53 [View at Publisher] [Google Scholar]
25. Monjezi M, Barari A, Abdi A. The Impact of Specific Physical Training on FGF-2 and VEGF-A Expression in Patients Post-Coronary Artery Bypass. J Bas Res Med Sci. 2024;11(3):56-65. [View at Publisher] [Google Scholar]
26. Soori R, SHarafi dehrahm F, CHoobine S, Valipour dehnou V. Effect of endurance training on VEGF protein level in tissue of cardiac muscle in STZ-induced diabetic Wistar rats. Yafte. 2018;20(3):110-24. [View at Publisher] [Google Scholar]
27. Yazdani F, Shahidi F, Karimi P. The effect of 8 weeks of high-intensity interval training and moderate-intensity continuous training on cardiac angiogenesis factor in diabetic male rats. J Physiol Biochem. 2020;76(2):291-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
28. Song BX, Azhar L, Koo GKY, Marzolini S, Gallagher D, Swardfager W, et al. The effect of exercise on blood concentrations of angiogenesis markers in older adults: a systematic review and meta-analysis. Neurobiol Aging. 2024:135:15-25. [View at Publisher] [DOI] [PMID] [Google Scholar]
29. Salgueiro RB, Gerlinger-Romero F, Guimarães-Ferreira L, de Castro Barbosa T, Nunes MT. Exercise training reverses the negative effects of chronic L-arginine supplementation on insulin sensitivity. Life Sci. 2017;191:17-23. [View at Publisher] [DOI] [PMID] [Google Scholar]
30. Zhang J, Yao M, Xia S, Zeng F, Liu Q. Systematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: implications for cellular adaptation and therapeutic strategies in cancer. Cell Mol Biol Lett. 2025;30(1):2. [View at Publisher] [DOI] [PMID] [Google Scholar]
31. Hall B, Żebrowska A, Sikora M, Siatkowski S, Robins A. The Effect of High-Intensity Interval Exercise on Short-Term Glycaemic Control, Serum Level of Key Mediator in Hypoxia and Pro-Inflammatory Cytokines in Patients with Type 1 Diabetes-An Exploratory Case Study. Nutrients. 2023;15(17):3749. [View at Publisher] [DOI] [PMID] [Google Scholar]
32. Figarella K, Kim J, Ruan W, Mills T, Eltzschig HK, Yuan X. Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome. Front Immunol. 2024;15:1328565. [View at Publisher] [DOI] [PMID] [Google Scholar]
33. Chen H, Guo L. Exercise in Diabetic Cardiomyopathy: Its Protective Effects and Molecular Mechanism. Int J Mol Sci. 2025;26(4):1465. [View at Publisher] [DOI] [PMID] [Google Scholar]
34. Firouzyar F, Shamlou Kazemi S, Hemmati Afif A. The Effect of High-Intensity Interval Training on Antioxidant Factors in Women with Type 2 Diabetes. JEHS. 2022;2(3):1-14. [View at publisher] [DOI] [Google Scholar]
35. Zhao L, Hu H, Zhang L, Liu Z, Huang Y, Liu Q, et al. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (2020). 2024;5(4):e516. [View at publisher] [DOI] [PMID] [Google Scholar]
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