Exercise induced cardioprotective effects and related molecular mechanisms
-
摘要: 心血管疾病仍是目前全球疾病负担的主要原因。缺乏身体活动是心血管疾病的可控危险因素之一,在临床实践中,运动被推荐作为心血管疾病预防和康复的重要手段。运动有助于降低心血管疾病患病风险,并且能够改善缺血性心脏病、心力衰竭等心血管疾病患者的预后以及健康相关生活质量,运动还可以改善蒽环类药物导致的心脏毒性。尽管运动诱导的心血管保护机制尚未完全阐明,人们已通过动物运动模型对相关机制进行广泛研究。在研究中,可将运动作为一种预处理使运动后心脏对病理刺激表现出抵抗作用;也可在疾病发生后进行运动干预,一定程度上缓解心脏损伤并维持心脏功能。从机制上讲,运动诱导的心脏保护作用是多方面的,这种保护作用与运动促进心脏生理性肥大,抑制病理性肥大,促进心肌细胞增殖,减少心肌细胞凋亡,改善心脏纤维化以及促进心脏血管生成有关。运动诱导的心脏保护作用相关分子机制涉及胰岛素样生长因子1(IGF-1)/磷酸肌醇3-激酶(PI3K)/蛋白激酶B(AKT)、神经调节素1(NRG1)/酪氨酸激酶受体(ErbB)、Hippo等信号通路以及肌因子、运动诱导肽、Sirtuin蛋白、外泌体和miRNA等分子。本文将从上述方面对运动诱导的心脏保护作用及相关分子机制进行阐述,以期为心脏疾病的防治和运动康复研究提供思路。Abstract: Cardiovascular disease (CVD) is still the main cause of the global burden of disease at present. Physical inactivity is one of the controllable risk factors for CVD, and in clinical practice, exercise is recommended as an important means of CVD prevention and rehabilitation. Exercise is beneficial in reducing the risk of CVD and improves outcomes as well as health-related quality of life in patients with CVD such as ischemic heart disease and heart failure, and it also ameliorates anthracycline-induced cardiotoxicity. Although the mechanism of exercise-induced cardiovascular protection has not been fully elucidated, the related mechanisms have been extensively studied by animal exercise models. In research, exercise may be used as a preconditioning to render the post exercise heart resistant to pathological stimuli; Exercise intervention can also be performed after the occurrence of the disease, to a certain extent, alleviating cardiac injury and maintaining cardiac function. Mechanistically, exercise-induced cardioprotection is multifaceted and this protective effect is associated with exercise promoting physiological cardiac hypertrophy, inhibiting pathological hypertrophy, promoting cardiomyocyte proliferation, reducing cardiomyocyte apoptosis, improving cardiac fibrosis, and promoting angiogenesis in the heart. The molecular mechanisms involved in exercise-induced cardioprotection involve signaling pathways such as IGF-1/PI3K/Akt, NRG1/ErbB, and Hippo, as well as molecules such as myokines, exercise-induced peptides, sirtuin, exosomes, and miRNAs. In this review, the cardioprotective effects induced by exercise and related molecular mechanisms will be elaborated from the above aspects, in the hope of providing ideas for the prevention and treatment of cardiac diseases and exercise rehabilitation research.
-
Key words:
- Exercise /
- Cardiac protection /
- Cardiac hypertrophy /
- Cardiomyocytes /
- Cardiac fibrosis /
- Angiogenesis
-
[1] LAVIE C J, OZEMEK C, CARBONE S, et al. Sedentary behavior, exercise, and cardiovascular health[J]. Circ Res, 2019, 124(5): 799-815. doi: 10.1161/CIRCRESAHA.118.312669 [2] 陈凌云, 秦琼, 王丽娟, 等. 分级运动康复训练在慢性心力衰竭患者的临床应用效果[J]. 中华全科医学, 2022, 20(8): 1339-1342. doi: 10.16766/j.cnki.issn.1674-4152.002591CHEN L Y, QIN Q, WANG L J, et al. Clinical application effect study of graded exercise rehabilitation training in patients with chronic heart failure[J]. Chinese Journal of General Practice, 2022, 20(8): 1339-1342. doi: 10.16766/j.cnki.issn.1674-4152.002591 [3] 汪蕾, 蔡濛, 邓晓惠, 等. 心肺康复运动对老年急性心肌梗死患者经皮冠状动脉介入术后心肺功能及心脏舒张功能的影响[J]. 中国医药, 2021, 16(3): 321-325. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYG202103001.htmWANG L, CAI M, DENG X H, et al. Effects of cardiopulmonary rehabilitation exercise on cardiopulmonary function and diastolic function in elderly patients with acute myocardial infarction after percutaneous coronary intervention[J]. China Medicine, 2021, 16(3): 321-325. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYG202103001.htm [4] SCHVTTLER D, CLAUSS S, WECKBACH L T, et al. Molecular mechanisms of cardiac remodeling and regeneration in physical exercise[J]. Cells, 2019, 8(10): 1128. doi: 10.3390/cells8101128 [5] ESSANDOH K, DENG S, WANG X, et al. Tsg101 positively regulates physiologic-like cardiac hypertrophy through FIP3-mediated endosomal recycling of IGF-1R[J]. FASEB J, 2019, 33(6): 7451-7466. doi: 10.1096/fj.201802338RR [6] WEEKS K L, THAM Y K, YILDIZ S G, et al. FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K[J]. Am J Physiol Heart Circ Physiol, 2021, 320(4): H1470-H1485. doi: 10.1152/ajpheart.00838.2020 [7] MA M, CHEN W, HUA Y, et al. Aerobic exercise ameliorates cardiac hypertrophy by regulating mitochondrial quality control and endoplasmic reticulum stress through M(2) AChR[J]. J Cell Physiol, 2021, 236(9): 6581-6596. doi: 10.1002/jcp.30342 [8] GAO R, WANG L, BEI Y, et al. Long Noncoding RNA cardiac physiological hypertrophy-associated regulator induces cardiac physiological hypertrophy and promotes functional recovery after myocardial ischemia-reperfusion injury[J]. Circulation, 2021, 144(4): 303-317. doi: 10.1161/CIRCULATIONAHA.120.050446 [9] LI H, TRAGER L E, LIU X, et al. lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth[J]. Circulation, 2022, 145(16), 1218-1233. doi: 10.1161/CIRCULATIONAHA.121.056850 [10] GHOLIPOUR M, TABRIZI A. The role of Hippo signaling pathway in physiological cardiac hypertrophy[J]. Bioimpacts, 2020, 10(4): 251-257. [11] 胡东红, 黄晓霞, 郑灿坤, 等. 运动性心肌肥厚预适应的抗肥厚记忆及其与交感神经活性的关系[J]. 南方医科大学学报, 2021, 41(4): 495-503. https://www.cnki.com.cn/Article/CJFDTOTAL-DYJD202104004.htmHU D H, HUANG X X, ZHENG C K, et al. Contribution of sympathetic activation to antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy in mice[J]. Journal of Southern Medical University, 2021, 41(4): 495-503. https://www.cnki.com.cn/Article/CJFDTOTAL-DYJD202104004.htm [12] LIN H, ZHU Y, ZHENG C, et al. Antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy is mediated by the long noncoding RNA Mhrt779[J]. Circulation, 2021, 143(23): 2277-2292. doi: 10.1161/CIRCULATIONAHA.120.047000 [13] VUJIC A, LERCHENMVLLER C, WU T D, et al. Exercise induces new cardiomyocyte generation in the adult mammalian heart[J]. Nat Commun, 2018, 9(1): 1659. doi: 10.1038/s41467-018-04083-1 [14] CAI M X, SHI X C, CHEN T, et al. Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model[J]. Life Sci, 2016, 149(6): 1-9. [15] 邢维新, 田振军. 运动训练诱导大鼠心肌HGF和TGF-β1表达对心肌细胞增殖的影响[J]. 山东体育学院学报, 2018, 34(6): 84-90. doi: 10.14104/j.cnki.1006-2076.2018.06.015XING W X, TIAN Z J. Effect of exercise training on the expression of HGF and TGF-β1 on the proliferation of myocardial cells in rats[J]. Journal of Shandong Sport University, 2018, 34(6): 84-90. doi: 10.14104/j.cnki.1006-2076.2018.06.015 [16] BO W, MA Y, XI Y, et al. The roles of FGF21 and ALCAT1 in aerobic exercise-induced cardioprotection of postmyocardial infarction mice[J]. Oxid Med Cell Longev, 2021, 2021: 8996482. DOI: 10.1155/2021/8996482. [17] TAO R H, KOBAYASHI M, YANG Y, et al. Exercise inhibits doxorubicin-induced damage to cardiac vessels and activation of Hippo/YAP-mediated apoptosis[J]. Cancers (Basel), 2021, 13(11): 2740. doi: 10.3390/cancers13112740 [18] ZHANG X, HU C, KONG C Y, et al. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT[J]. Cell Death Differ, 2020, 27(2): 540-555. doi: 10.1038/s41418-019-0372-z [19] LU L, MA J, TANG J, et al. Irisin attenuates myocardial ischemia/reperfusion-induced cardiac dysfunction by regulating ER-mitochondria interaction through a mitochondrial ubiquitin ligase-dependent mechanism[J]. Clin Transl Med, 2020, 10(5): e166. DOI: 10.1002/ctm2.166. [20] OTAKA N, SHIBATA R, OHASHI K, et al. Myonectin is an exercise-induced myokine that protects the heart from ischemia-reperfusion injury[J]. Circ Res, 2018, 123(12): 1326-1338. doi: 10.1161/CIRCRESAHA.118.313777 [21] ZHANG L, WANG X, ZHANG H, et al. Exercise-induced peptide EIP-22 protect myocardial from ischaemia/reperfusion injury via activating JAK2/STAT3 signalling pathway[J]. J Cell Mol Med, 2021, 25(7): 3560-3572. doi: 10.1111/jcmm.16441 [22] CHENG Z, ZHANG H, ZHANG L, et al. Exercise-induced peptide TAG-23 protects cardiomyocytes from reperfusion injury through regulating PKG-cCbl interaction[J]. Basic Res Cardiol, 2021, 116(1): 41. doi: 10.1007/s00395-021-00878-4 [23] DONNIACUO M, URBANEK K, NEBBIOSO A, et al. Cardioprotective effect of a moderate and prolonged exercise training involves sirtuin pathway[J]. Life Sci, 2019, 222(7): 140-147. [24] PIRES D S J, MONCEAUX K, GUILBERT A, et al. SIRT1 protects the heart from ER stress-induced injury by promoting eEF2K/eEF2-dependent autophagy[J]. Cells, 2020, 9(2): 426. doi: 10.3390/cells9020426 [25] XU J J, CUI J, LIN Q, et al. Protection of the enhanced Nrf2 deacetylation and its downstream transcriptional activity by SIRT1 in myocardial ischemia/reperfusion injury[J]. Int J Cardiol, 2021, 342(21): 82-93. [26] ZHAO D, SUN Y, TAN Y, et al. Short-duration swimming exercise after myocardial infarction attenuates cardiac dysfunction and regulates mitochondrial quality control in aged mice[J]. Oxid Med Cell Longev, 2018, 2018: 4079041. DOI: 10.1155/2018/4079041. [27] HOU Z, QIN X, HU Y, et al. Longterm exercise-derived exosomal miR-342-5p: a novel exerkine for cardioprotection[J]. Circ Res, 2019, 124(9): 1386-1400. doi: 10.1161/CIRCRESAHA.118.314635 [28] BEI Y, LU D, BǍR C, et al. miR-486 attenuates cardiac ischemia/reperfusion injury and mediates the beneficial effect of exercise for myocardial protection[J]. Mol Ther, 2022, 30(4): 1675-1691. doi: 10.1016/j.ymthe.2022.01.031 [29] SUN X H, WANG X, ZHANG Y, et al. Exosomes of bone-marrow stromal cells inhibit cardiomyocyte apoptosis under ischemic and hypoxic conditions via miR-486-5p targeting the PTEN/PI3K/AKT signaling pathway[J]. Thromb Res, 2019, 177(4): 23-32. [30] MA Y, KUANG Y, BO W, et al. Exercise training alleviates cardiac fibrosis through increasing fibroblast growth factor 21 and regulating TGF-β1-Smad2/3-MMP2/9 signaling in mice with myocardial infarction[J]. Int J Mol Sci, 2021, 22(22): 12341. doi: 10.3390/ijms222212341 [31] CHEN X, LI H, WANG K, et al. Aerobic exercise ameliorates myocardial inflammation, fibrosis and apoptosis in high-fat-diet rats by inhibiting P2X7 purinergic receptors[J]. Front Physiol, 2019, 10: 1286. DOI: 10.3389/fphys.2019.01286. [32] ZHOU J, TIAN G, QUAN Y, et al. Inhibition of P2X7 purinergic receptor ameliorates cardiac fibrosis by suppressing NLRP3/IL-1β pathway[J]. Oxid Med Cell Longev, 2020, 2020: 7956274. DOI: 10.1155/2020/7956274. [33] PAN J A, ZHANG H, LIN H, et al. Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells[J]. Redox Biol, 2021, 46(9): 102120. DOI: 10.1016/j.redox.2021.102120. [34] WANG B L, JIN H, HAN X Q, et al. Involvement of brain-derived neurotrophic factor in exercise-induced cardioprotection of post-myocardial infarction rats[J]. Int J Mol Med, 2018, 42(5): 2867-2880. [35] SONG W, LIANG Q, CAI M, et al. HIF-1α-induced up-regulation of microRNA-126 contributes to the effectiveness of exercise training on myocardial angiogenesis in myocardial infarction rats[J]. J Cell Mol Med, 2020, 24(22): 12970-12979. doi: 10.1111/jcmm.15892 [36] TIAN X, ZHOU N, YUAN J, et al. Heat shock transcription factor 1 regulates exercise-induced myocardial angiogenesis after pressure overload via HIF-1α/VEGF pathway[J]. J Cell Mol Med, 2020, 24(3): 2178-2188. doi: 10.1111/jcmm.14872 [37] LIAO Q, QU S, TANG L X, et al. Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis[J]. Acta Pharmacol Sin, 2019, 40(10): 1314-1321. doi: 10.1038/s41401-019-0230-z [38] GOETZE J P, BRUNEAU B G, RAMOS H R, et al. Cardiac natriuretic peptides[J]. Nat Rev Cardiol, 2020, 17(11): 698-717. [39] FOINQUINOS A, BATKAI S, GENSCHEL C, et al. Preclinical development of a miR-132 inhibitor for heart failure treatment[J]. Nat Commun, 2020, 11(1): 633. [40] DA R A, TEIXEIRA G R, PINTO A P, et al. Excessive training induces molecular signs of pathologic cardiac hypertrophy[J]. J Cell Physiol, 2018, 233(11): 8850-8861.
点击查看大图
计量
- 文章访问数: 317
- HTML全文浏览量: 76
- PDF下载量: 8
- 被引次数: 0