Effect of timing window of remote ischemic conditioning training on myocardial cell death profile in myocardial ischemia-reperfusion injury_West China Medical Journal

Authors：

DONG Qiumeng , HUANG Jiayi ,  ZHENG Yu

Department of Rehabilitation Medicine, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu 210029, P. R. China;

Corresponding?author：

ZHENG Yu, Email: zhengyu8710@163.com

Keywords：

Remote ischemic conditioning; timing window; ischemia-reperfusion injury; cell death profile; cardiac rehabilitation

DOI：

10.7507/1002-0179.202604331

Video：

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Objective To investigate the effects of different intervention time windows of remote ischemic conditioning (RIC) training on cardiac function, myocardial fibrosis, and the myocardial cell death profiles after myocardial ischemia-reperfusion injury (IRI) in mice. Methods C57BL/6 male mice were randomly divided into the sham surgery group, IRI group, pre-ischemia 3-day intervention group, immediate intervention during the ischemic period after left anterior descending artery ligation group, post-reperfusion immediate intervention group, and post-reperfusion 3-day intervention group, with 6 mice in each group. RIC intervention involved limb ischemia for 5 minutes followed by reperfusion for 5 minutes, repeated for 5 cycles. The heart function, myocardial infarction area, degree of myocardial fibrosis, and expression of apoptosis-related proteins, pyroptosis-related proteins, and ferroptosis-related proteins in myocardial tissue were measured. Results Compared with the sham surgery group, the IRI group showed a decrease in left ventricular ejection fraction and left ventricular fractional shortening (P<0.05). Compared with the IRI group, all RIC training intervention groups showed varying degrees of improvement in cardiac function (P<0.05), and the deposition of myocardial collagen fibers was reduced. Compared with the IRI group, the pre-ischemia 3-day intervention group showed a decrease in Bax and cleaved-caspase-3 protein expression and an increase in Bcl-2 protein expression (P<0.05). The myocardial infarction area was reduced in the immediate intervention during the ischemic period after left anterior descending artery ligation group (P<0.05). The expression of GPX4 and xCT proteins increased in the post-reperfusion immediate intervention group (P<0.05). The expression of GPX4 and xCT proteins increased, while the expression of nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 and caspase-1 proteins decreased in the post-reperfusion 3-day intervention group (P<0.05). Conclusion Different time windows of RIC can alleviate cardiac dysfunction and myocardial fibrosis in mice with myocardial IRI to varying degrees, and their protective effects vary across different intervention time windows.

Citation： DONG Qiumeng, HUANG Jiayi, ZHENG Yu. Effect of timing window of remote ischemic conditioning training on myocardial cell death profile in myocardial ischemia-reperfusion injury. West China Medical Journal, 2026, 41(6): 907-913. doi: 10.7507/1002-0179.202604331 Copy

1.	Global Burden of Cardiovascular Diseases and Risks 2023 Collaborators. Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023. J Am Coll Cardiol, 2025, 86(22): 2167-2243.
2.	Wang HY, Zhang R, Dou K, et al. Left main bifurcation stenting: impact of residual ischaemia on cardiovascular mortality. Eur Heart J, 2023, 44(41): 4324-4336.
3.	國家心血管病中心, 中國心血管健康與疾病報告編寫組, 胡盛壽. 中國心血管健康與疾病報告 2024 概要. 中國循環雜志, 2025, 40(6): 521-559.
4.	Kitsis RN. Regulated cell death in myocardial infarction. Circ Res, 2025, 137(6): 924-929.
5.	Gao R, Lv C, Qu Y, et al. Remote ischemic conditioning mediates cardio-protection after myocardial ischemia/reperfusion injury by reducing 4-HNE levels and regulating autophagy via the ALDH2/SIRT3/HIF1α signaling pathway. J Cardiovasc Transl Res, 2024, 17(1): 169-182.
6.	Arnold JR, P Vanezis A, Rodrigo GC, et al. Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction. Basic Res Cardiol, 2022, 117(1): 23.
7.	White SK, Frohlich GM, Sado DM, et al. Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv, 2015, 8(1): 178-188.
8.	Rentoukas I, Giannopoulos G, Kaoukis A, et al. Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Interv, 2010, 3(1): 49-55.
9.	Jia P, Ji Q, Zou Z, et al. Effect of delayed remote ischemic preconditioning on acute kidney injury and outcomes in patients undergoing cardiac surgery: a randomized clinical trial. Circulation, 2024, 150(17): 1366-1376.
10.	Nie X, Li C, Hu S, et al. An appropriate loading control for western blot analysis in animal models of myocardial ischemic infarction. Biochem Biophys Rep, 2017, 12: 108-113.
11.	Johny E, Dutta P. Left coronary artery ligation: a surgical murine model of myocardial infarction. J Vis Exp, 2022, 9(186): 10.
12.	Ghanim D, Kusniec F, Kinany W, et al. Left circumflex coronary artery as the culprit vessel in st-segment-elevation myocardial infarction. Tex Heart Inst J, 2017, 44(5): 320-325.
13.	Han D, Wang J, Wen L, et al. Remote limb ischemic postconditioning protects against ischemic stroke via modulating microglia/macrophage polarization in mice. J Immunol Res, 2021, 2021: 6688053.
14.	Abdul-Ghani S, Fleishman AN, Khaliulin I, et al. Remote ischemic preconditioning triggers changes in autonomic nervous system activity: implications for cardioprotection. Physiol Rep, 2017, 5(3): e13085.
15.	Marzuca-Nassr GN, Murata GM, Martins AR, et al. Balanced diet-fed fat-1 transgenic mice exhibit lower hindlimb suspension-induced soleus muscle atrophy. Nutrients, 2017, 9(10): 1100.
16.	Pickard JM, Davidson SM, Hausenloy DJ, et al. Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning. Basic Res Cardiol, 2016, 111(4): 50.
17.	Yang Y, Schena GJ, Wang T, et al. Postsurgery echocardiography can predict the amount of ischemia-reperfusion injury and the resultant scar size. Am J Physiol Heart Circ Physiol, 2021, 320(2): H690-H698.
18.	Zhu Y, Jiao Z, Bei Y. ALDH2: essential mediator for the remote ischemic conditioning strategy to reduce myocardial ischemia/reperfusion injury. J Cardiovasc Transl Res, 2024, 17(1): 167-168.
19.	Kundumani-Sridharan V, Subramani J, Owens C, et al. Nrg1β released in remote ischemic preconditioning improves myocardial perfusion and decreases ischemia/reperfusion injury via ErbB2-mediated rescue of endothelial nitric oxide synthase and abrogation of Trx2 autophagy. Arterioscler Thromb Vasc Biol, 2021, 41(8): 2293-2314.
20.	Pang Q, Meng X, Zhou Z, et al. Temporal regulation of genetic programs governing multiple cell death during myocardial ischemia-reperfusion injury. Front Genet, 2025, 16: 1632867.
21.	Buja LM. Pathobiology of myocardial and cardiomyocyte injury in ischemic heart disease: perspective from seventy years of cell injury research. Exp Mol Pathol, 2024, 140: 104944.
22.	Li Y, Chen B, Yang X, et al. S100a8/a9 signaling causes mitochondrial dysfunction and cardiomyocyte death in response to ischemic/reperfusion injury. Circulation, 2019, 140(9): 751-764.
23.	Buja LM. Pathobiology of myocardial ischemia and reperfusion injury: models, modes, molecular mechanisms, modulation, and clinical applications. Cardiol Rev, 2023, 31(5): 252-264.
24.	Cai W, Liu L, Shi X, et al. Alox15/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis. Circulation, 2023, 147(19): 1444-1460.
25.	Qi L, Yi J, Ji Y, et al. Network of cell death in myocardial ischemia-reperfusion injury: mechanisms and targeted therapeutic strategies. Biochem Pharmacol, 2026, 250(2): 117999.
26.	Cheng XF, He ST, Zhong GQ, et al. Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation. BMC Cardiovasc Disord, 2023, 23(1): 58.
27.	Benavides S, Palavecino R, Riquelme JA, et al. Inhibition of NOX2 or NLRP3 inflammasome prevents cardiac remote ischemic preconditioning. Front Physiol, 2024, 14: 1327402.
28.	邢大一, 張涌, 李毅, 等. 雙下肢缺血后處理保護再灌注心肌時效性及對線粒體通路調控的研究. 中國病理生理雜志, 2024, 40(4): 637-645.
29.	Yang ZJ, Zhang WF, Jin QQ, et al. Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via the AMP-activated protein kinase-mammalian target of rapamycin-transcription factor EB-connexin 43 axis. Am J Pathol, 2024, 194(10): 1857-1878.
30.	Lassen TR, Just J, Hjortbak MV, et al. Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles. Basic Res Cardiol, 2021, 116(1): 16.
31.	Liu G, Lv Y, Wang Y, et al. Remote ischemic preconditioning reduces mitochondrial apoptosis mediated by calpain 1 activation in myocardial ischemia-reperfusion injury through calcium channel subunit Cacna2d3. Free Radic Biol Med, 2024, 212: 80-93.
32.	Qi L, Yi J, Shen Y, et al. The myocardial ischemic cascade network and multi-target synergistic interventions: from molecular mechanisms to therapeutic innovations. Biochem Pharmacol, 2026, 246: 117704.
33.	Hausenloy DJ, Iliodromitis EK, Andreadou I, et al. Investigating the signal transduction pathways underlying remote ischemic conditioning in the porcine heart. Cardiovasc Drugs Ther, 2012, 26(2): 87-93.
34.	Hausenloy DJ, Kharbanda RK, M?ller UK, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet, 2019, 394(10207): 1415-1424.
35.	Bonanni A, Signori A, Alicino C, et al. Volatile anesthetics versus propofol for cardiac surgery with cardiopulmonary bypass: meta-analysis of randomized trials. Anesthesiology, 2020, 132(6): 1429-1446.

1. Global Burden of Cardiovascular Diseases and Risks 2023 Collaborators. Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023. J Am Coll Cardiol, 2025, 86(22): 2167-2243.
2. Wang HY, Zhang R, Dou K, et al. Left main bifurcation stenting: impact of residual ischaemia on cardiovascular mortality. Eur Heart J, 2023, 44(41): 4324-4336.
3. 國家心血管病中心, 中國心血管健康與疾病報告編寫組, 胡盛壽. 中國心血管健康與疾病報告 2024 概要. 中國循環雜志, 2025, 40(6): 521-559.
4. Kitsis RN. Regulated cell death in myocardial infarction. Circ Res, 2025, 137(6): 924-929.
5. Gao R, Lv C, Qu Y, et al. Remote ischemic conditioning mediates cardio-protection after myocardial ischemia/reperfusion injury by reducing 4-HNE levels and regulating autophagy via the ALDH2/SIRT3/HIF1α signaling pathway. J Cardiovasc Transl Res, 2024, 17(1): 169-182.
6. Arnold JR, P Vanezis A, Rodrigo GC, et al. Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction. Basic Res Cardiol, 2022, 117(1): 23.
7. White SK, Frohlich GM, Sado DM, et al. Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv, 2015, 8(1): 178-188.
8. Rentoukas I, Giannopoulos G, Kaoukis A, et al. Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Interv, 2010, 3(1): 49-55.
9. Jia P, Ji Q, Zou Z, et al. Effect of delayed remote ischemic preconditioning on acute kidney injury and outcomes in patients undergoing cardiac surgery: a randomized clinical trial. Circulation, 2024, 150(17): 1366-1376.
10. Nie X, Li C, Hu S, et al. An appropriate loading control for western blot analysis in animal models of myocardial ischemic infarction. Biochem Biophys Rep, 2017, 12: 108-113.
11. Johny E, Dutta P. Left coronary artery ligation: a surgical murine model of myocardial infarction. J Vis Exp, 2022, 9(186): 10.
12. Ghanim D, Kusniec F, Kinany W, et al. Left circumflex coronary artery as the culprit vessel in st-segment-elevation myocardial infarction. Tex Heart Inst J, 2017, 44(5): 320-325.
13. Han D, Wang J, Wen L, et al. Remote limb ischemic postconditioning protects against ischemic stroke via modulating microglia/macrophage polarization in mice. J Immunol Res, 2021, 2021: 6688053.
14. Abdul-Ghani S, Fleishman AN, Khaliulin I, et al. Remote ischemic preconditioning triggers changes in autonomic nervous system activity: implications for cardioprotection. Physiol Rep, 2017, 5(3): e13085.
15. Marzuca-Nassr GN, Murata GM, Martins AR, et al. Balanced diet-fed fat-1 transgenic mice exhibit lower hindlimb suspension-induced soleus muscle atrophy. Nutrients, 2017, 9(10): 1100.
16. Pickard JM, Davidson SM, Hausenloy DJ, et al. Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning. Basic Res Cardiol, 2016, 111(4): 50.
17. Yang Y, Schena GJ, Wang T, et al. Postsurgery echocardiography can predict the amount of ischemia-reperfusion injury and the resultant scar size. Am J Physiol Heart Circ Physiol, 2021, 320(2): H690-H698.
18. Zhu Y, Jiao Z, Bei Y. ALDH2: essential mediator for the remote ischemic conditioning strategy to reduce myocardial ischemia/reperfusion injury. J Cardiovasc Transl Res, 2024, 17(1): 167-168.
19. Kundumani-Sridharan V, Subramani J, Owens C, et al. Nrg1β released in remote ischemic preconditioning improves myocardial perfusion and decreases ischemia/reperfusion injury via ErbB2-mediated rescue of endothelial nitric oxide synthase and abrogation of Trx2 autophagy. Arterioscler Thromb Vasc Biol, 2021, 41(8): 2293-2314.
20. Pang Q, Meng X, Zhou Z, et al. Temporal regulation of genetic programs governing multiple cell death during myocardial ischemia-reperfusion injury. Front Genet, 2025, 16: 1632867.
21. Buja LM. Pathobiology of myocardial and cardiomyocyte injury in ischemic heart disease: perspective from seventy years of cell injury research. Exp Mol Pathol, 2024, 140: 104944.
22. Li Y, Chen B, Yang X, et al. S100a8/a9 signaling causes mitochondrial dysfunction and cardiomyocyte death in response to ischemic/reperfusion injury. Circulation, 2019, 140(9): 751-764.
23. Buja LM. Pathobiology of myocardial ischemia and reperfusion injury: models, modes, molecular mechanisms, modulation, and clinical applications. Cardiol Rev, 2023, 31(5): 252-264.
24. Cai W, Liu L, Shi X, et al. Alox15/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis. Circulation, 2023, 147(19): 1444-1460.
25. Qi L, Yi J, Ji Y, et al. Network of cell death in myocardial ischemia-reperfusion injury: mechanisms and targeted therapeutic strategies. Biochem Pharmacol, 2026, 250(2): 117999.
26. Cheng XF, He ST, Zhong GQ, et al. Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation. BMC Cardiovasc Disord, 2023, 23(1): 58.
27. Benavides S, Palavecino R, Riquelme JA, et al. Inhibition of NOX2 or NLRP3 inflammasome prevents cardiac remote ischemic preconditioning. Front Physiol, 2024, 14: 1327402.
28. 邢大一, 張涌, 李毅, 等. 雙下肢缺血后處理保護再灌注心肌時效性及對線粒體通路調控的研究. 中國病理生理雜志, 2024, 40(4): 637-645.
29. Yang ZJ, Zhang WF, Jin QQ, et al. Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via the AMP-activated protein kinase-mammalian target of rapamycin-transcription factor EB-connexin 43 axis. Am J Pathol, 2024, 194(10): 1857-1878.
30. Lassen TR, Just J, Hjortbak MV, et al. Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by extracellular vesicles. Basic Res Cardiol, 2021, 116(1): 16.
31. Liu G, Lv Y, Wang Y, et al. Remote ischemic preconditioning reduces mitochondrial apoptosis mediated by calpain 1 activation in myocardial ischemia-reperfusion injury through calcium channel subunit Cacna2d3. Free Radic Biol Med, 2024, 212: 80-93.
32. Qi L, Yi J, Shen Y, et al. The myocardial ischemic cascade network and multi-target synergistic interventions: from molecular mechanisms to therapeutic innovations. Biochem Pharmacol, 2026, 246: 117704.
33. Hausenloy DJ, Iliodromitis EK, Andreadou I, et al. Investigating the signal transduction pathways underlying remote ischemic conditioning in the porcine heart. Cardiovasc Drugs Ther, 2012, 26(2): 87-93.
34. Hausenloy DJ, Kharbanda RK, M?ller UK, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet, 2019, 394(10207): 1415-1424.
35. Bonanni A, Signori A, Alicino C, et al. Volatile anesthetics versus propofol for cardiac surgery with cardiopulmonary bypass: meta-analysis of randomized trials. Anesthesiology, 2020, 132(6): 1429-1446.

West China Medical Journal

Effect of timing window of remote ischemic conditioning training on myocardial cell death profile in myocardial ischemia-reperfusion injury

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