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CARDIOLOGY / BASIC RESEARCH
High-intensity interval training: unveiling seven key genes mediating cardioprotection in myocardial infarction
1
College of Sport and Health, Guangxi Normal University, Guilin, Guangxi Zhuang Autonomous Region, China
Submission date: 2025-04-29
Final revision date: 2025-08-05
Acceptance date: 2025-08-05
Online publication date: 2025-10-26
Corresponding author
Fenglin Peng
College of Sport and Health Guangxi Normal University Guilin 541006 Guangxi Zhuang Autonomous Region China
College of Sport and Health Guangxi Normal University Guilin 541006 Guangxi Zhuang Autonomous Region China
Arch Med Sci 2025;21(6):2476-2492
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Myocardial infarction (MI) is a leading cause of mortality, driven by inflammation and cardiac remodeling. While high-intensity interval training (HIIT) improves MI outcomes, its molecular mechanisms remain poorly defined, limiting therapeutic optimization. This study aimed to identify molecular targets and signaling pathways modulated by HIIT in MI, uncovering new therapeutic strategies for cardiovascular recovery.
Material and methods:
Differential gene expression analysis of the GSE66360 dataset, comprising circulating endothelial cells from MI patients (n = 49) and healthy controls (n = 50), identified 481 DEGs. Cross-referencing with 717 HIIT-related genes from GeneCards revealed 39 overlapping genes. PPI and functional enrichment analyses highlighted seven hub genes: TNF, IL1B, MMP9, TLR4, ICAM1, TLR2, and CXCL1. These were validated by RT-qPCR in MI patients and controls (n = 20 each). MI was induced in rats (n = 8 per group), followed by an 8-week HIIT regimen. Infarct size, fibrosis, and protein expression were assessed using TTC staining, histology, and Western blot.
Results:
We identified 481 DEGs in MI (351 upregulated, 130 downregulated; FDR-adjusted p < 0.05, |log2 fold change| > 1), with 39 overlapping HIIT-related genes. Seven hub genes (TNF, IL1B, MMP9, TLR4, ICAM1, TLR2, CXCL1) were upregulated in MI patients (p < 0.001, RT-qPCR). In MI rats, HIIT reduced infarct size by 32% (p < 0.01), decreased fibrosis and inflammatory cell infiltration (p < 0.05), and downregulated all seven hub genes (p < 0.05). Enrichment analyses linked these genes to TNF and TLR pathways, highlighting HIIT’s anti-inflammatory effects.
Conclusions:
HIIT protects the heart after MI by targeting inflammatory and remodeling pathways, providing a basis for precision cardiovascular therapy.
Myocardial infarction (MI) is a leading cause of mortality, driven by inflammation and cardiac remodeling. While high-intensity interval training (HIIT) improves MI outcomes, its molecular mechanisms remain poorly defined, limiting therapeutic optimization. This study aimed to identify molecular targets and signaling pathways modulated by HIIT in MI, uncovering new therapeutic strategies for cardiovascular recovery.
Material and methods:
Differential gene expression analysis of the GSE66360 dataset, comprising circulating endothelial cells from MI patients (n = 49) and healthy controls (n = 50), identified 481 DEGs. Cross-referencing with 717 HIIT-related genes from GeneCards revealed 39 overlapping genes. PPI and functional enrichment analyses highlighted seven hub genes: TNF, IL1B, MMP9, TLR4, ICAM1, TLR2, and CXCL1. These were validated by RT-qPCR in MI patients and controls (n = 20 each). MI was induced in rats (n = 8 per group), followed by an 8-week HIIT regimen. Infarct size, fibrosis, and protein expression were assessed using TTC staining, histology, and Western blot.
Results:
We identified 481 DEGs in MI (351 upregulated, 130 downregulated; FDR-adjusted p < 0.05, |log2 fold change| > 1), with 39 overlapping HIIT-related genes. Seven hub genes (TNF, IL1B, MMP9, TLR4, ICAM1, TLR2, CXCL1) were upregulated in MI patients (p < 0.001, RT-qPCR). In MI rats, HIIT reduced infarct size by 32% (p < 0.01), decreased fibrosis and inflammatory cell infiltration (p < 0.05), and downregulated all seven hub genes (p < 0.05). Enrichment analyses linked these genes to TNF and TLR pathways, highlighting HIIT’s anti-inflammatory effects.
Conclusions:
HIIT protects the heart after MI by targeting inflammatory and remodeling pathways, providing a basis for precision cardiovascular therapy.
REFERENCES (54)
1.
Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J 2022; 43: 716-99.
2.
Sui Y, Zhang W, Tang T, et al. Insulin-like growth factor-II overexpression accelerates parthenogenetic stem cell differentiation into cardiomyocytes and improves cardiac function after acute myocardial infarction in mice. Stem Cell Res Ther 2020; 11: 86.
3.
Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol 2015; 5: 1841-75.
4.
Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J 2023; 44: 3720-826.
5.
Welt FGP, Batchelor W, Spears JR, et al. Reperfusion injury in patients with acute myocardial infarction: JACC Scientific Statement. J Am Coll Cardiol 2024; 83: 2196-213.
6.
Bozkurt B, Fonarow GC, Goldberg LR, et al. Cardiac rehabilitation for patients with heart failure: JACC Expert Panel. J Am Coll Cardiol 2021; 77: 1454-69.
7.
Tucker WJ, Fegers-Wustrow I, Halle M, et al. Exercise for primary and secondary prevention of cardiovascular disease: JACC Focus Seminar 1/4. J Am Coll Cardiol 2022; 80: 1091-106.
8.
Myers J, Kokkinos P, Nyelin E. Physical activity, cardiorespiratory fitness, and the metabolic syndrome. Nutrients 2019; 11: 1652.
9.
McGregor G, Powell R, Begg B, et al. High-intensity interval training in cardiac rehabilitation: a multi-centre randomized controlled trial. Eur J Prev Cardiol 2023; 30: 745-55.
10.
Taylor JL, Holland DJ, Keating SE, et al. Short-term and long-term feasibility, safety, and efficacy of high-intensity interval training in cardiac rehabilitation: the FITR Heart Study Randomized Clinical Trial. JAMA Cardiol 2020; 5: 1382-9.
11.
Reed JL, Terada T, Cotie LM, et al. The effects of high-intensity interval training, Nordic walking and moderate-to-vigorous intensity continuous training on functional capacity, depression and quality of life in patients with coronary artery disease enrolled in cardiac rehabilitation: a randomized controlled trial (CRX study). Prog Cardiovasc Dis 2022; 70: 73-83.
12.
Wang B, Zhou R, Wang Y, et al. Effect of high-intensity interval training on cardiac structure and function in rats with acute myocardial infarct. Biomed Pharmacother 2020; 131: 110690.
13.
Naderi N, Hemmatinafar M, Gaeini AA, et al. High-intensity interval training increase GATA4, CITED4 and c-Kit and decreases C/EBPβ in rats after myocardial infarction. Life Sci 2019; 221: 319-26.
14.
Dun Y, Thomas RJ, Smith JR, et al. High-intensity interval training improves metabolic syndrome and body composition in outpatient cardiac rehabilitation patients with myocardial infarction. Cardiovasc Diabetol 2019; 18: 104.
15.
Aispuru-Lanche GR, Gallego-Muñoz M, Jayo-Montoya JA, et al. Low-Volume and high-intensity aerobic interval training may attenuate dysfunctional ventricular remodeling after myocardial infarction: data from the INTERFARCT study. Rev Cardiovasc Med 2023; 24: 20.
16.
Qin Y, Bundhun PK, Yuan ZL, Chen MH. The effect of high-intensity interval training on exercise capacity in post-myocardial infarction patients: a systematic review and meta-analysis. Eur J Prev Cardiol 2022; 29: 475-84.
17.
Zheng M, Liu C, Lv Y, et al. Comparisons of high intensity interval training and continuous training on metabolomic alteration and cardiac function in male adolescent rats. Front Physiol 2022; 13: 900661.
18.
Bielecka-Dabrowa A, Trzmielak D, Sakowicz A, et al. Gender differences in efficiency of the telemedicine care of heart failure patients. The results from the TeleEduCare-HF study. Arch Med Sci 2024; 20: 1797-808.
19.
Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41: 407-77.
20.
Dibben GO, Faulkner J, Oldridge N, et al. Exercise-based cardiac rehabilitation for coronary heart disease: a meta-analysis. Eur Heart J 2023; 44: 452-69.
21.
Corrigendum to: The association between daily step count and all-cause and cardiovascular mortality: a meta-analysis. Eur J Prev Cardiol 2023; 30: 2045.
22.
Zandecki L, Janion M, Sadowski M, et al. Associations of changes in patient characteristics and management with decrease in mortality rates of men and women with ST-elevation myocardial infarction – a propensity score-matched analysis. Arch Med Sci 2020; 16: 772-80.
23.
Wu J, Yan J, Hua Z, et al. Identification of molecular signatures in acute myocardial infarction based on integrative analysis of proteomics and transcriptomics. Genomics 2023; 115: 110701.
24.
Zhang J, Huang C, Meng X, et al. Effects of different exercise interventions on cardiac function in rats with myocardial infarction. Heart Lung Circ 2021; 30: 773-80.
25.
Trachsel LD, David LP, Gayda M, et al. The impact of high-intensity interval training on ventricular remodeling in patients with a recent acute myocardial infarction-a randomized training intervention pilot study. Clin Cardiol 2019; 42: 1222-31.
26.
Heiat F, Ahmadi A, Shojaeifard M. The exercise preconditioning effect on cardiac tissue injury following induction of myocardial infarction in male rats. Biomed Res Int 2023; 2023: 3631458.
27.
Lu K, Wang L, Wang C, et al. Effects of high-intensity interval versus continuous moderate-intensity aerobic exercise on apoptosis, oxidative stress and metabolism of the infarcted myocardium in a rat model. Mol Med Rep 2015; 12: 2374-82.
28.
Nori P, Haghshenas R, Aftabi Y, Akbari H. Comparison of moderate-intensity continuous training and high-intensity interval training effects on the Ido1-KYN-Ahr axis in the heart tissue of rats with occlusion of the left anterior descending artery. Sci Rep 2023; 13: 3721.
29.
Oral O. Nitric oxide and its role in exercise physiology. J Sports Med Phys Fitness 2021; 61: 1208-11.
30.
Allen JD. Nitric oxide as a mediator of exercise performance: NO pain NO gain. Nitric Oxide 2023; 136-137: 8-11.
31.
Kingwell BA. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. Faseb J 2000; 14: 1685-96.
32.
Adams V, Linke A. Impact of exercise training on cardiovascular disease and risk. Biochim Biophys Acta Mol Basis Dis 2019; 1865: 728-34.
33.
Zhang Q, Wang L, Wang S, et al. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther 2022; 7: 78.
34.
Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2016; 119: 91-112.
35.
Chen DQ, Kong XS, Shen XB, et al. Identification of differentially expressed genes and signaling pathways in acute myocardial infarction based on integrated bioinformatics analysis. Cardiovasc Ther 2019; 2019: 8490707.
36.
Kehmeier ES, Lepper W, Kropp M, et al. TNF-, myocardial perfusion and function in patients with ST-segment elevation myocardial infarction and primary percutaneous coronary intervention. Clin Res Cardiol 2012; 101: 815-27.
37.
Zheng W, Zhou T, Zhang Y, et al. Simplified (2)-macroglobulin as a TNF- inhibitor for inflammation alleviation in osteoarthritis and myocardial infarction therapy. Biomaterials 2023; 301: 122247.
38.
Sugano M, Koyanagi M, Tsuchida K, et al. In vivo gene transfer of soluble TNF-alpha receptor 1 alleviates myocardial infarction. FASEB J 2002; 16: 1421-2.
39.
Somasuntharam I, Yehl K, Carroll SL, et al. Knockdown of TNF- by DNAzyme gold nanoparticles as an anti-inflammatory therapy for myocardial infarction. Biomaterials 2016; 83: 12-22.
40.
Wang Y, Guo Y, Xu Y, et al. HIIT Ameliorates inflammation and lipid metabolism by regulating macrophage polarization and mitochondrial dynamics in the liver of type 2 diabetes mellitus mice. Metabolites 2022; 13: 14.
41.
Rhibi F, Zouhal H, Lira FS, et al. Inflammatory cytokines and metabolic responses to high-intensity intermittent training: effect of the exercise intensity. Biol Sport 2022; 39: 263-72.
42.
Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 2018; 15: 203-14.
43.
Van Tassell BW, Varma A, Salloum FN, et al. Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice. J Cardiovasc Pharmacol 2010; 55: 117-22.
44.
Iyer RP, Jung M, Lindsey ML. MMP-9 signaling in the left ventricle following myocardial infarction. Am J Physiol Heart Circ Physiol 2016; 311: H190-8.
45.
Goerg J, Sommerfeld M, Greiner B, et al. Low-dose empagliflozin improves systolic heart function after myocardial infarction in rats: regulation of MMP9, NHE1, and SERCA2a. Int J Mol Sci 2021; 22: 5437.
46.
Ma Y, Kuang Y, Bo W, et al. Exercise training alleviates cardiac fibrosis through increasing fibroblast growth factor 21 and regulating TGF-1-Smad2/3-MMP2/9 signaling in mice with myocardial infarction. Int J Mol Sci 2021; 22: 12341.
47.
Singh V, Kaur R, Kumari P, et al. ICAM-1 and VCAM-1: gatekeepers in various inflammatory and cardiovascular disorders. Clin Chim Acta 2023; 548: 117487.
48.
Yu J, Liu Y, Peng W, Xu Z. Serum VCAM-1 and ICAM-1 measurement assists for MACE risk estimation in ST-segment elevation myocardial infarction patients. J Clin Lab Anal 2022; 36: e24685.
49.
Papathanasiou JV, Petrov I, Tsekoura D, et al. Does group-based high-intensity aerobic interval training improve the inflammatory status in patients with chronic heart failure? Eur J Phys Rehabil Med 2022; 58: 242-50.
50.
Sandanger Ø, Gao E, Ranheim T, et al. NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun 2016; 469: 1012-20.
51.
Zhai Y, Ao L, Yao Q, et al. Elevated expression of TLR2 in aging hearts exacerbates cardiac inflammatory response and adverse remodeling following ischemia and reperfusion injury. Front Immunol 2022; 13: 891570.
52.
Valdes-Marquez E, Clarke R, Hill M, et al. Proteomic profiling identifies novel independent relationships between inflammatory proteins and myocardial infarction. Eur J Prev Cardiol 2023; 30: 583-91.
53.
Hojman P, Brolin C, Nørgaard-Christensen N, et al. IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity. Am J Physiol Endocrinol Metab 2019; 316: E940-7.
54.
Banach M, Fogacci F, Atanasov AG, et al. A 360° perspective on cardiovascular prevention: the International Lipid Expert Panel SiMple tIps for the heaLthy hEart (ILEP-SMILE). Arch Med Sci 2025; 21: 711-8.
| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
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