Calcium Sensitive Receptors Mediate Signaling Pathways in Myocardial Injury

doi:10.12114/j.issn.1007-9572.2024.0117

Abstract

Abstract:

Calcium sensing receptor (CaSR) is a G-protein-coupled receptor that induces highly diffused messengers to activate various cellular responses. Recently, it has been suggested that CaSR mediates signal communication among endoplasmic reticulum, mitochondria, and nucleus, and this process is associated with myocardial injury. Cardiomyocytes are permanent cells and do not regenerate. Therefore, this paper will focus on the relevant regulatory mechanisms of CaSR in myocardial injury, comb out the complex intracellular signal transduction network mediated by CASR, and provide ideas for finding new therapeutic targets for myocardial injury.

Key words: Myocardial injury, Myocardial hypertrophy, Myocardial fibrosis, Calcium sensitive receptors

摘要：

钙敏感受体（CaSR）是一种G蛋白偶联受体，可以诱导高度扩散的信使以激活各种细胞反应。最近研究认为CaSR介导内质网、线粒体、细胞核之间的信号通信，且此过程与心肌损伤相关。心肌细胞为永久细胞，不可再生。因此，本文将重点介绍CaSR在心肌损伤中的相关调控机制，梳理其介导的复杂细胞内信号转导网络，为寻找心肌损伤治疗新靶点提供思路。

关键词: 心肌损伤, 心肌肥大, 心肌纤维化, 钙敏感受体

CLC Number:

R 541

SHEN Mingmei,LYU Yujiao,ZHANG Shangbo, et al. Calcium Sensitive Receptors Mediate Signaling Pathways in Myocardial Injury[J]. Chinese General Practice, 2025, 28(18): 2301-2306. DOI: 10.12114/j.issn.1007-9572.2024.0117.
沈明妹,吕俞娇,张尚博等. 钙敏感受体在心肌损伤中介导的信号通路研究进展[J]. 中国全科医学, 2025, 28(18): 2301-2306. DOI: 10.12114/j.issn.1007-9572.2024.0117.

Figures/Tables 2

References 49

[1]	SEJERSTED O M. Calcium controls cardiac function—by all means![J]. J Physiol，2011，589（Pt 12）：2919-2920.
[2]	MARCHI S，PATERGNANI S，MISSIROLI S，et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death[J]. Cell Calcium，2018，69：62-72. DOI：10.1016/j.ceca.2017.05.003.
[3]	NING B，GUO C Z，KONG A Q，et al. Calcium signaling mediates cell death and crosstalk with autophagy in kidney disease[J]. Cells，2021，10（11）：3204. DOI：10.3390/cells10113204.
[4]	SRIDHAR K C，HERSCH N，DREISSEN G，et al. Calcium mediated functional interplay between myocardial cells upon laser-induced single-cell injury：an in vitro study of cardiac cell death signaling mechanisms[J]. Cell Commun Signal，2020，18（1）：191. DOI：10.1186/s12964-020-00689-5.
[5]	GORVIN C M. Molecular and clinical insights from studies of calcium-sensing receptor mutations[J]. J Mol Endocrinol，2019，63（2）：R1-16. DOI：10.1530/JME-19-0104.
[6]	LEACH K，HANNAN F M，JOSEPHS T M，et al. International union of basic and clinical pharmacology. CVⅢ. calcium-sensing receptor nomenclature，pharmacology，and function[J]. Pharmacol Rev，2020，72（3）：558-604.
[7]	YOTTASAN P，CHU T，CHHETRI P D，et al. Repurposing calcium-sensing receptor activator drug cinacalcet for ADPKD treatment[J]. Transl Res，2024，265：17-25. DOI：10.1016/j.trsl.2023.10.005.
[8]	GORKHALI R，TIAN L，DONG B，et al. Extracellular calcium alters calcium-sensing receptor network integrating intracellular calcium-signaling and related key pathway[J]. Sci Rep，2021，11（1）：20576. DOI：10.1038/s41598-021-00067-2.
[9]	IRNATEN M，DUFF A，CLARK A，et al. Intra-cellular calcium signaling pathways（PKC，RAS/RAF/MAPK，PI3K）in Lamina cribrosa cells in glaucoma[J]. J Clin Med，2020，10（1）：62. DOI：10.3390/jcm10010062.
[10]	LIU C，LI H M，ZHENG H S，et al. CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during ischemia/reperfusion[J]. Int J Mol Med，2019，44（3）：1117-1126. DOI：10.3892/ijmm.2019.4255.
[11]	DONG S Y，TENG Z Y，LU F H，et al. Post-conditioning protects cardiomyocytes from apoptosis via PKC（epsilon）-interacting with calcium-sensing receptors to inhibit endo（sarco）plasmic reticulum-mitochondria crosstalk[J]. Mol Cell Biochem，2010，341（1/2）：195-206. DOI：10.1007/s11010-010-0450-5.
[12]	CHEN L，SHI D Z，GUO M. The roles of PKC-δ and PKC-ε in myocardial ischemia/reperfusion injury[J]. Pharmacol Res，2021，170：105716. DOI：10.1016/j.phrs.2021.105716.
[13]	MIAO L N，PAN D，SHI J H，et al. Role and mechanism of PKC-δ for cardiovascular disease：current status and perspective[J]. Front Cardiovasc Med，2022，9：816369.
[14]	DONG S Y，TENG Z Y，LU F H，et al. Post-conditioning protects cardiomyocytes from apoptosis via PKC（epsilon）-interacting with calcium-sensing receptors to inhibit endo（sarco）plasmic reticulum-mitochondria crosstalk[J]. Mol Cell Biochem，2010，341（1/2）：195-206. DOI：10.1007/s11010-010-0450-5.
[15]	DING M G，SHI R，FU F，et al. Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway[J]. J Adv Res，2023，47：151-162.
[16]	ZHU Q X，LUO Y，WEN Y T，et al. Semaglutide inhibits ischemia/reperfusion-induced cardiomyocyte apoptosis through activating PKG/PKCε/ERK1/2 pathway[J]. Biochem Biophys Res Commun，2023，647：1-8. DOI：10.1016/j.bbrc.2023.01.049.
[17]	ZENG J Y，PAN Y，CUI B H，et al. Calcium-sensing receptors in human peripheral T lymphocytes and AMI：cause and effect[J]. Int J Mol Med，2018，42（6）：3437-3446. DOI：10.3892/ijmm.2018.3924.
[18]	SUETOMI T，MIYAMOTO S，BROWN J H. Inflammation in nonischemic heart disease：initiation by cardiomyocyte CaMKⅡ and NLRP3 inflammasome signaling[J]. Am J Physiol Heart Circ Physiol，2019，317（5）：H877-890. DOI：10.1152/ajpheart.00223.2019.
[19]	SUETOMI T，WILLEFORD A，BRAND C S，et al. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca²⁺/calmodulin-dependent protein kinase Ⅱ δ signaling in cardiomyocytes are essential for adverse cardiac remodeling[J]. Circulation，2018，138（22）：2530-2544. DOI：10.1161/CIRCULATIONAHA.118.034621.
[20]	REN Z Q，YANG K，ZHAO M，et al. Calcium-sensing receptor on neutrophil promotes myocardial apoptosis and fibrosis after acute myocardial infarction via NLRP3 inflammasome activation[J]. Can J Cardiol，2020，36（6）：893-905. DOI：10.1016/j.cjca.2019.09.026.
[21]	ZENG J Y，DU J J，PAN Y，et al. Calcium-sensing receptor in human peripheral blood T lymphocytes is involved in the AMI onset and progression through the NF-κB signaling pathway[J]. Int J Mol Sci，2016，17（9）：1397. DOI：10.3390/ijms17091397.
[22]	ZENG J Y，CHENG Y Y，XIE W L，et al. Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation[J]. Cell Mol Life Sci，2024，81（1）：19. DOI：10.1007/s00018-023-05051-9.
[23]	RUSSO M A，SANSONE L，CARNEVALE I，et al. One special question to start with：can HIF/NFkB be a target in inflammation?[J]. Endocr Metab Immune Disord Drug Targets，2015，15（3）：171-185.
[24]	WEI Q，BIAN Y P，YU F C，et al. Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model[J]. J Biomed Res，2016，30（6）：490-495. DOI：10.7555/JBR.30.20160110.
[25]	KUMAR S，WANG G，LIU W J，et al. Hypoxia-induced mitogenic factor promotes cardiac hypertrophy via calcium-dependent and hypoxia-inducible factor-1α mechanisms[J]. Hypertension，2018，72（2）：331-342. DOI：10.1161/HYPERTENSIONAHA.118.10845.
[26]	ZHONG X，LIU J，LU F H，et al. Calcium sensing receptor regulates cardiomyocyte function through nuclear calcium[J]. Cell Biol Int，2012，36（10）：937-943.
[27]	LU M L，LENG B，HE X，et al. Calcium sensing receptor-related pathway contributes to cardiac injury and the mechanism of astragaloside Ⅳ on cardioprotection[J]. Front Pharmacol，2018，9：1163. DOI：10.3389/fphar.2018.01163.
[28]	WILKINS B J，DAI Y S，BUENO O F，et al. Calcineurin/NFAT coupling participates in pathological，but not physiological，cardiac hypertrophy[J]. Circ Res，2004，94（1）：110-118. DOI：10.1161/01.RES.0000109415.17511.18.
[29]	CHEN P，WEN Z，SHI W，et al. Effects of sodium ferulate on cardiac hypertrophy are via the casr-mediated signaling pathway[J]. Front Pharmacol，2021，12：674570. DOI：10.3389/fphar.2021.674570.
[30]	LIN K H，KUO W W，SHIBU M A，et al. E2/ER β enhances calcineurin protein degradation and PI3K/akt/MDM2 signal transduction to inhibit ISO-induced myocardial cell apoptosis[J]. Int J Mol Sci，2017，18（4）：892.
[31]	BOGDANOVA E，BERESNEVA O，GALKINA O，et al. Myocardial hypertrophy and fibrosis are associated with cardiomyocyte beta-catenin and TRPC6/calcineurin/NFAT signaling in spontaneously hypertensive rats with 5/6 nephrectomy[J]. Int J Mol Sci，2021，22（9）：4645. DOI：10.3390/ijms22094645.
[32]	QIAN L J，HONG J，ZHANG Y M，et al. Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β-catenin pathway in mice[J]. Cell Physiol Biochem，2018，46（6）：2551-2560.
[33]	张翥，陶亮亮，刘品刚，等. Wnt/β-catenin抑制剂XAV939对心肌梗死大鼠心肌纤维化的影响[J]. 岭南心血管病杂志，2021，27（2）：214-218. DOI：10.3969/j.issn.1007-9688.2021.02.19.
[34]	XING L J，ZHANG H，MAJUMDER K，et al. γ-glutamylvaline prevents low-grade chronic inflammation via activation of a calcium-sensing receptor pathway in 3T3-L1Mouse adipocytes[J]. J Agric Food Chem，2019，67（30）：8361-8369.
[35]	ZHOU P，ZHANG X Y，GUO M Q，et al. Ginsenoside Rb1 ameliorates CKD-associated vascular calcification by inhibiting the Wnt/β-catenin pathway[J]. J Cell Mol Med，2019，23（10）：7088-7098. DOI：10.1111/jcmm.14611.
[36]	朱烨静，周惠丹，崔小英，等. 钙敏感受体在大剂量瑞芬太尼诱导卵巢癌裸鼠心肌损伤中的作用机制研究[J]. 浙江医学，2021，43（7）：696-699，725，后插1. DOI：10.12056/j.issn.1006-2785.2021.43.7.2020-1895.
[37]	ZHU Y，CHI J，CAI S，et al. High-dose remifentanil exacerbates myocardial ischemia-reperfusion injury through activation of calcium-sensing receptor-mediated pyroptosis[J]. Int J Med Sci. 2023，20（12）：1570-1583. DOI：10.7150/ijms.83207
[38]	FRANGOGIANNIS N G. Cardiac fibrosis：cell biological mechanisms，molecular pathways and therapeutic opportunities[J]. Mol Aspects Med，2019，65：70-99.
[39]	YUAN H，FAN Y Q，WANG Y H，et al. Calcium-sensing receptor promotes high glucose-induced myocardial fibrosis via upregulation of the TGF-β1/Smads pathway in cardiac fibroblasts[J]. Mol Med Rep，2019，20（2）：1093-1102.
[40]	YUAN H，XU J Y，XU X Y，et al. Calhex231 alleviates high glucose-induced myocardial fibrosis via inhibiting itch-ubiquitin proteasome pathway in vitro[J]. Biol Pharm Bull，2019，42（8）：1337-1344. DOI：10.1248/bpb.b19-00090.
[41]	RONG Y，ZHOU X，GUO Z L，et al. Activation of Kir2.1 improves myocardial fibrosis by inhibiting Ca²⁺ overload and the TGF-β1/Smad signaling pathway[J]. Acta Biochim Biophys Sin，2023，55（5）：749-757. DOI：10.3724/abbs.2023083.
[42]	徐娜，王跃虹，姜晓姝，等. 增加CaSR表达减轻2型糖尿病大鼠心肌纤维化的机制[J]. 哈尔滨医科大学学报，2021，55（1）：7-10. DOI：10.3969/j.issn.1000-1905.2021.01.002.
[43]	ZHAO J，LU N，QU Y，et al. Calcium-sensing receptor-mediated macrophage polarization improves myocardial remodeling in spontaneously hypertensive rats[J]. Exp Biol Med（Maywood），2024，249：10112. DOI：10.3389/ebm.2024.10112.
[44]	ZHANG T，TANG N，XI D M，et al. Calcimimetic R568 improved cardiac remodeling by classic and novel renin-angiotensin system in spontaneously hypertensive rats[J]. Exp Biol Med，2019，244（10）：789-801. DOI：10.1177/1535370219854325.
[45]	CHLEILAT E，PETHE A，PFEIFER D，et al. TGF-β signaling regulates SLC8A3 expression and prevents oxidative stress in developing midbrain dopaminergic and dorsal raphe serotonergic neurons[J]. Int J Mol Sci，2020，21（8）：2735.
[46]	MASCHARAK S，DESJARDINS-PARK H E，DAVITT M F，et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring[J]. Science，2021，372（6540）：eaba2374. DOI：10.1126/science.aba2374.
[47]	GYÖRFI A H，MATEI A E，FUCHS M，et al. Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation[J]. J Exp Med，2021，218（9）：e20201916.
[48]	HAMANO N，KOMABA H，FUKAGAWA M. Etelcalcetide for the treatment of secondary hyperparathyroidism[J]. Expert Opin Pharmacother，2017，18（5）：529-534.
[49]	陈盈宇，王鸥，邢小平. 钙敏感受体拮抗剂（溶钙素）的临床应用[J]. 中华骨质疏松和骨矿盐疾病杂志，2021，14（5）：553-559. DOI：10.3969/j.issn.1674-2591.2021.05.016.

	缺血再灌注	急性心肌梗死	高血压（心肌肥大）	糖尿病心肌病（心肌纤维化）
PKC-δ易位	+	+
CaN/NFAT	+		+
TGF-β1/Smads				+
CaSR/Wnt/β-catenin				+
NF-κB	+	+	+

	缺血再灌注	急性心肌梗死	高血压（心肌肥大）	糖尿病心肌病（心肌纤维化）
PKC-δ易位	+	+
CaN/NFAT	+		+
TGF-β1/Smads				+
CaSR/Wnt/β-catenin				+
NF-κB	+	+	+