Research progress on signaling pathways and drug intervention in radiation-induced heart disease

doi:10.11958/20231637

Abstract

Abstract:

Radiation-induced heart disease (RIHD) is a cardiotoxic event secondary to radiotherapy for thoracic tumors, and has become another unfavorable factor affecting the health of cancer patients in addition to cancer cytotoxicity. Signal transduction plays an important role in cellular information exchange. RIHD can induce dysregulation of signaling pathways and hinder the normal function of pathways, thus causing myocardial tissue to undergo lesions such as apoptosis, oxidative stress and fibrosis. Now, we review the relevant pathways that are dysregulated in the development of RIHD, as well as the regulatory effects of drug intervention on these pathways, in order to provide a reference basis for the prevention and treatment of RIHD.

Key words: chemoradiotherapy, tumor, radiation-induced heart disease, signaling pathways, pharmacological interventions

CLC Number:

R541.9

Figures/Tables 1

References 37

[1]	KARLSTAEDT A, MOSLEHI J, DE BOER R A. Cardio-onco-metabolism:metabolic remodelling in cardiovascular disease and cancer[J]. Nat Rev Cardiol, 2022, 19(6):414-425. doi:10.1038/s41569-022-00698-6.
[2]	SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer statistics,2022[J]. CA Cancer J Clin, 2022, 72(1):7-33. doi:10.3322/caac.21708.
[3]	WANG K X, YE C, YANG X, et al. New insights into the understanding of mechanisms of radiation-induced heart disease[J]. Curr Treat Options Oncol, 2023, 24(1):12-29. doi:10.1007/s11864-022-01041-4.
[4]	YANG E H, MARMAGKIOLIS K, BALANESCU D V, et al. Radiation-induced vascular disease-a state-of-the-art review[J]. Front Cardiovasc Med, 2021, 8:652761. doi:10.3389/fcvm.2021.652761.
[5]	SÁRKÖZY M, VARGA Z, GÁSPÁR R, et al. Pathomechanisms and therapeutic opportunities in radiation-induced heart disease:from bench to bedside[J]. Clin Res Cardiol, 2021, 110(4):507-531. doi:10.1007/s00392-021-01809-y.
[6]	BELZILE-DUGAS E, EISENBERG M J. Radiation-induced cardiovascular disease:review of an underrecognized pathology[J]. J Am Heart Assoc, 2021, 10(18):e021686. doi:10.1161/JAHA.121.021686.
[7]	杨华菊, 张益, 彭鸥, 等. 放射性心脏损伤:现状与挑战[J]. 四川大学学报(医学版), 2022, 53(6):1127-1134.
	YANG H J, ZHANG Y, PENG O, et al. Radiation-induced heart disease:current status and challenges[J]. J Sichuan Univ(Med Sci), 2022, 53(6):1127-1134. doi:10.12182/20221160302.
[8]	DREYFUSS A D, VELALOPOULOU A, AVGOUSTI H, et al. Preclinical models of radiation-induced cardiac toxicity:potential mechanisms and biomarkers[J]. Front Oncol, 2022, 12:920867. doi:10.3389/fonc.2022.920867.
[9]	CHENG W, CUI C, LIU G, et al. NF-κB,a potential therapeutic target in cardiovascular diseases[J]. Cardiovasc Drugs Ther, 2023, 37(3):571-584. doi:10.1007/s10557-022-07362-8.
[10]	ZHANG X, CHEN X, WANG A, et al. Yiqi jiedu decoction attenuates radiation injury of spermatogenic cells via suppressing IκBα/NF-κB pathway-induced excessive autophagy and apoptosis[J]. J Ethnopharmacol, 2024, 318(Pt A):116903. doi:10.1016/j.jep.2023.116903.
[11]	VERMA S, DUTTA A, DAHIYA A, et al. Quercetin-3-Rutinoside alleviates radiation-induced lung inflammation and fibrosis via regulation of NF-κB/TGF-β1 signaling[J]. Phytomedicine, 2022, 99:154004. doi:10.1016/j.phymed.2022.154004.
[12]	何平, 赵燕, 王海东, 等. 氟比洛芬酯对放射性心脏损伤模型大鼠NF-κB/TGF-β1信号通路的影响[J]. 中国免疫学杂志, 2023, 39(5):945-950.
	HE P, ZHAO Y, WANG H D, et al. Effects of flurbiprofen axetil on NF-κB/TGF-β1 signaling pathway in rats with radiation-induced heart disease[J]. Chinese Journal of Immunology, 2023, 39(5):945-950. doi:10.3969/j.issn.1000-484X.2023.05.009.
[13]	WU Y, LIU L, LV S, et al. Pyrrolidine dithiocarbamate might mitigate radiation-induced heart damage at an early stage in rats[J]. Front Pharmacol, 2022, 13:832045. doi: 10.3389/fphar.2022.832045.
[14]	LI L, NIE X, ZHANG P, et al. Dexrazoxane ameliorates radiation-induced heart disease in a rat model[J]. Aging (Albany NY), 2021, 13(3):3699-3711. doi:10.18632/aging.202332.
[15]	WANG J, HU K, CAI X, et al. Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis[J]. Acta Pharm Sin B, 2022, 12(1):18-32. doi:10.1016/j.apsb.2021.07.023.
[16]	PENG Y, WANG Y, ZHOU C, et al. PI3K/Akt/mTOR pathway and its role in cancer therapeutics:are we making headway?[J]. Front Oncol, 2022, 12:819128. doi:10.3389/fonc.2022.819128.
[17]	KOVÁCS M G, KOVÁCS Z Z A, VARGA Z, et al. Investigation of the antihypertrophic and antifibrotic effects of losartan in a rat model of radiation-induced heart disease[J]. Int J Mol Sci, 2021, 22(23):12963. doi:10.3390/ijms222312963.
[18]	常娟. 当归红芪提取物对X线诱导乳鼠心肌成纤维细胞纤维化的相关机制及干预作用研究[D]. 兰州: 甘肃中医药大学, 2022.
	CHANG J. Study on the related mechanism and intervention effect of extract of Radix Angelica Sinensis and Radix Hedysari on fibrosis in myocardial fibroblast of neonatal rats after X-ray radiation[D]. Lanzhou: Gansu University of Chinese Medicine, 2022. doi:10.27026/d.cnki.ggszc.2022.000001.
[19]	GUO Z Y, TANG Y, CHENG Y C. Exosomes as targeted delivery drug system:advances in exosome loading,surface functionalization and potential for clinical application[J]. Curr Drug Deliv, 2024, 21(4):473-487. doi:10.2174/1567201819666220613150814.
[20]	CUI W W, YE C, WANG K X, et al. Momordica. charantia-derived extracellular vesicles-like nanovesicles protect cardiomyocytes against radiation injury via attenuating DNA damage and mitochondria dysfunction[J]. Front Cardiovasc Med, 2022, 9:864188. doi:10.3389/fcvm.2022.864188.
[21]	崔会程, 夏嫱. 昆虫抗菌肽抗炎活性及基于信号通路抗炎机制的研究进展[J]. 天津医药, 2022, 50(9):1002-1008.
	CUI H C, XIA Q. Research progress in anti-inflammatory activity of insect antimicrobial peptides and anti-inflammatory mechanism based on signal pathway[J]. Tianjin Med J, 2022, 50(9):1002-1008. doi:10.11958/20212862.
[22]	MA Y, NICOLET J. Specificity models in MAPK cascade signaling[J]. FEBS Open Bio, 2023, 13(7):1177-1192. doi:10.1002/2211-5463.13619.
[23]	GARCÍA-FLORES N, JIMÉNEZ-SUÁREZ J, GARNÉS-GARCÍA C, et al. P38 MAPK and radiotherapy:foes or friends?[J]. Cancers (Basel), 2023, 15(3):861. doi:10.3390/cancers15030861.
[24]	WANG G, MA L, WANG B, et al. Tanshinone IIA accomplished protection against radiation-induced cardiomyocyte injury by regulating the p38/p53 pathway[J]. Mediators Inflamm, 2022,2022:1478181. doi:10.1155/2022/1478181.
[25]	KIANG J G, CANNON G, OLSON M G, et al. Female mice are more resistant to the mixed-field (67% neutron + 33% gamma) radiation-induced injury in bone marrow and small intestine than male mice due to sustained increases in G-CSF and the Bcl-2/Bax ratio and lower miR-34a and MAPK Activation[J]. Radiat Res, 2022, 198(2):120-133. doi:10.1667/RADE-21-00201.1.
[26]	SHI X, YANG J, DENG S, et al. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies[J]. J Hematol Oncol, 2022, 15(1):135. doi:10.1186/s13045-022-01349-6.
[27]	AASHAQ S, BATOOL A, MIR S A, et al. TGF-β signaling:a recap of SMAD-independent and SMAD-dependent pathways[J]. J Cell Physiol, 2022, 237(1):59-85. doi:10.1002/jcp.30529.
[28]	冯张鑫. 大鼠心脏低剂量照射所致损伤及其早期检测指标[D]. 贵阳: 贵州医科大学, 2021.
	FENG Z X. Damage induced by low-dose irradiation of rat heart and its early detection indicators[D]. Guiyang: Guizhou Medical University, 2021. doi:10.27045/d.cnki.ggyyc.2021.000063.
[29]	ZHOU X, BAO W A, ZHU X, et al. 3,3'-Diindolylmethane attenuates inflammation and fibrosis in radiation-induced lung injury by regulating NF-κB/TGF-β/Smad signaling pathways[J]. Exp Lung Res, 2022, 48(3):103-113. doi:10.1080/01902148.2022.2052208.
[30]	ZHANG J, HE X, BAI X, et al. Protective effect of trimetazidine in radiation-induced cardiac fibrosis in mice[J]. J Radiat Res, 2020, 61(5):657-665. doi:10.1093/jrr/rraa043.
[31]	ARORA A, BHURIA V, SINGH S, et al. Amifostine analog,DRDE-30,alleviates radiation induced lung damage by attenuating inflammation and fibrosis[J]. Life Sci, 2022, 298:120518. doi:10.1016/j.lfs.2022.120518.
[32]	WANG Z, REN D, ZHENG P. The role of Rho/ROCK in epileptic seizure-related neuronal damage[J]. Metab Brain Dis, 2022, 37(4):881-887. doi:10.1007/s11011-022-00909-6.
[33]	GUAN G, CANNON R D, COATES D E, et al. Effect of the Rho-Kinase/ROCK signaling pathway on cytoskeleton components[J]. Genes(Basel), 2023, 14(2):272. doi:10.3390/genes14020272.
[34]	MONCEAU V, PASINETTI N, SCHUPP C, et al. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity[J]. Curr Drug Targets, 2010, 11(11):1395-1404. doi:10.2174/1389450111009011395.
[35]	邢喜平, 任春贞, 蒋虎刚, 等. 基于Rho/Rock通路探讨当归红芪多糖对辐射诱导大鼠H9C2心肌细胞的作用机制[J]. 辽宁中医杂志, 2021, 48(7):228-231.
	XING X P, REN C Z, JIANG H G, et al. Study on mechanism of angelica and hedysari polysaccharide on radiation-induced H9C2 cardiac cells based on Rho/Rock pathway[J]. Liaoning Journal of Traditional Chinese Medicine, 2021, 48(7):228-231. doi:10.13192/j.issn.1000-1719.2021.07.061.
[36]	ZHANG D M, DENG J J, WU Y G, et al. MicroRNA-223-3p protect against radiation-induced cardiac toxicity by alleviating myocardial oxidative stress and programmed cell death via targeting the AMPK pathway[J]. Front Cell Dev Biol, 2021, 9:801661. doi:10.3389/fcell.2021.801661.
[37]	HUANG Y, CHENG M, WANG X, et al. Dang Gui Bu Xue Tang,a conventional Chinese herb decoction,ameliorates radiation-induced heart disease via Nrf2/HMGB1 pathway[J]. Front Pharmacol, 2023, 13:1086206. doi:10.3389/fphar.2022.1086206.

通路	状态	功能
NF-κB/TGF-β1	激活	炎症、纤维化
PI3K/AKT	激活/抑制	纤维化、细胞凋亡、自噬
MAPK	激活/抑制	纤维化、细胞凋亡、氧化应激
TGF-β/Smad	激活	纤维化
Rho/ROCK	激活	纤维化、细胞凋亡、氧化应激
AMPK	激活/抑制	细胞凋亡、氧化应激、自噬
Nrf2/HMGB1	激活	纤维化
通路	干预药物	文献
NF-κB/TGF-β1	氟比洛芬酯、右丙亚胺、吡咯烷二硫代氨基甲酸盐	[12?-14]
PI3K/AKT	当归红芪提取物、氯沙坦、细胞外囊泡	[17-18，20]
MAPK	丹参酮ⅡA磺酸钠、左旋肉碱	[24-25]
TGF-β/Smad	曲美他嗪	[30]
Rho/ROCK	当归红芪多糖	[35]
AMPK	miRNA-223-3p	[36]
Nrf2/HMGB1	当归补血汤	[37]

通路	状态	功能
NF-κB/TGF-β1	激活	炎症、纤维化
PI3K/AKT	激活/抑制	纤维化、细胞凋亡、自噬
MAPK	激活/抑制	纤维化、细胞凋亡、氧化应激
TGF-β/Smad	激活	纤维化
Rho/ROCK	激活	纤维化、细胞凋亡、氧化应激
AMPK	激活/抑制	细胞凋亡、氧化应激、自噬
Nrf2/HMGB1	激活	纤维化
通路	干预药物	文献
NF-κB/TGF-β1	氟比洛芬酯、右丙亚胺、吡咯烷二硫代氨基甲酸盐	[12?-14]
PI3K/AKT	当归红芪提取物、氯沙坦、细胞外囊泡	[17-18，20]
MAPK	丹参酮ⅡA磺酸钠、左旋肉碱	[24-25]
TGF-β/Smad	曲美他嗪	[30]
Rho/ROCK	当归红芪多糖	[35]
AMPK	miRNA-223-3p	[36]
Nrf2/HMGB1	当归补血汤	[37]