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Research Article

Exosomal MiR-29a in Cardiomyocytes Induced by Angiotensin II Regulates Cardiac Microvascular Endothelial Cell Proliferation, Migration and Angiogenesis by Targeting VEGFA

Author(s): Guangzhao Li, Zhimei Qiu, Chaofu Li, Ranzun Zhao, Yu Zhang, Changyin Shen, Weiwei Liu, Xianping Long, Shaowei Zhuang, Yan Wang* and Bei Shi*

Volume 22, Issue 4, 2022

Published on: 01 April, 2022

Page: [331 - 341] Pages: 11

DOI: 10.2174/1566523222666220303102951

Price: $65

Abstract

Background: Exosomes released from cardiomyocytes (CMs) potentially play an important role in angiogenesis through microRNA (miR) delivery. Studies have reported an important role for miR-29a in regulating angiogenesis and pathological myocardial hypertrophy. However, whether CMderived exosomal miR-29a is involved in regulating cardiac microvascular endothelial cell (CMEC) homeostasis during myocardial hypertrophy has not been determined.

Methods: Angiotensin II (Ang II) was used to induce CM hypertrophy, and ultracentrifugation was then used to extract exosomes from a CM-conditioned medium. CMECs were cocultured with a conditioned medium in the presence or absence of exosomes derived from CMs (Nor-exos) or exosomes derived from angiotensin II-induced CMs (Ang II-exos). Moreover, a rescue experiment was performed using CMs or CMECs infected with miR-29a mimics or inhibitors. Tube formation assays, Transwell assays, and 5-ethynyl-20-deoxyuridine (EdU) assays were then performed to determine the changes in CMECs treated with exosomes. The miR-29a expression was measured by qRT-PCR, and Western blotting and flow cytometry assays were performed to evaluate the proliferation of CMECs.

Results: The results showed that Ang II-induced exosomal miR-29a inhibited the angiogenic ability, migratory function, and proliferation of CMECs. Subsequently, the downstream target gene of miR- 29a, namely, vascular endothelial growth factor (VEGFA), was detected by qRT-PCR and Western blotting, and the results verified that miR-29a targeted the inhibition of the VEGFA expression to subsequently inhibit the angiogenic ability of CMECs.

Conclusion: Our results suggest that exosomes derived from Ang II-induced CMs are involved in regulating CMCE proliferation, migration, and angiogenesis by targeting VEGFA through the transfer of miR-29a to CMECs.

Keywords: Cardiomyocyte hypertrophy, cardiomyocyte, cardiac microvascular endothelial cell, exosome, miR-29a, VEGFA.

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Graphical Abstract

[1]
Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 2006; 20(24): 3347-65.
[http://dx.doi.org/10.1101/gad.1492806] [PMID: 17182864]
[2]
van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest 2013; 123(1): 37-45.
[http://dx.doi.org/10.1172/JCI62839] [PMID: 23281408]
[3]
Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016; 97: 245-62.
[http://dx.doi.org/10.1016/j.yjmcc.2016.06.001] [PMID: 27262674]
[4]
Chiu AP, Wan A, Lal N, et al. Cardiomyocyte VEGF regulates endothelial cell GPIHBP1 to relocate lipoprotein lipase to the coronary lumen during diabetes mellitus. Arterioscler Thromb Vasc Biol 2016; 36(1): 145-55.
[http://dx.doi.org/10.1161/ATVBAHA.115.306774] [PMID: 26586663]
[5]
Wang Y, Zhao R, Shen C, et al. Exosomal CircHIPK3 released from hypoxia-induced cardiomyocytes regulates cardiac angiogenesis after myocardial infarction. Oxid Med Cell Longev 2020; 2020: 8418407.
[http://dx.doi.org/10.1155/2020/8418407] [PMID: 32733638]
[6]
Ribeiro-Rodrigues TM, Laundos TL, Pereira-Carvalho R, et al. Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. Cardiovasc Res 2017; 113(11): 1338-50.
[http://dx.doi.org/10.1093/cvr/cvx118] [PMID: 28859292]
[7]
Xu MY, Ye ZS, Song XT, Huang RC. Differences in the cargos and functions of exosomes derived from six cardiac cell types: a systematic review. Stem Cell Res Ther 2019; 10(1): 194.
[http://dx.doi.org/10.1186/s13287-019-1297-7] [PMID: 31248454]
[8]
Qiao L, Hu S, Liu S, et al. microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. J Clin Invest 2019; 129(6): 2237-50.
[http://dx.doi.org/10.1172/JCI123135] [PMID: 31033484]
[9]
Singla DK, Johnson TA, Tavakoli Dargani Z. Exosome treatment enhances anti-inflammatory M2 macrophages and reduces inflammation-induced pyroptosis in doxorubicin-induced cardiomyopathy. Cells 2019; 8(10): 1224.
[http://dx.doi.org/10.3390/cells8101224] [PMID: 31600901]
[10]
Dai Yuxiang. M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia_reperfusion injury via inhibiting TXNIP and the TLR4_NF-κB_NLRP3 inflammasome signaling pathway. J Mol Cell 2019; 5(1): 65-79.
[11]
Roncarati R, Viviani Anselmi C, Losi MA, et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2014; 63(9): 920-7.
[http://dx.doi.org/10.1016/j.jacc.2013.09.041] [PMID: 24161319]
[12]
Garikipati VNS, Verma SK, Cheng Z, et al. Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat Commun 2019; 10(1): 4317.
[http://dx.doi.org/10.1038/s41467-019-11777-7] [PMID: 31541092]
[13]
Wang Y, Zhao R, Liu W, et al. Exosomal circHIPK3 released from hypoxia-pretreated cardiomyocytes regulates oxidative damage in cardiac microvascular endothelial cells via the miR-29a/IGF-1 pathway. Oxid Med Cell Longev 2019; 2019: 7954657.
[http://dx.doi.org/10.1155/2019/7954657] [PMID: 31885817]
[14]
Deng W, Wang Y, Long X, et al. miR-21 reduces hydrogen peroxide-induced apoptosis in c-kit+ cardiac stem cells in vitro through PTEN/PI3K/Akt signaling. Oxid Med Cell Longev 2016; 2016: 5389181.
[http://dx.doi.org/10.1155/2016/5389181] [PMID: 27803763]
[15]
Garcia NA, Ontoria-Oviedo I, González-King H, Diez-Juan A, Sepúlveda P. Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells. PLoS One 2015; 10(9): e0138849.
[http://dx.doi.org/10.1371/journal.pone.0138849] [PMID: 26393803]
[16]
Sun J, Shen H, Shao L, et al. HIF-1α overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis. Stem Cell Res Ther 2020; 11(1): 373.
[http://dx.doi.org/10.1186/s13287-020-01881-7] [PMID: 32859268]
[17]
Zhang X, Sai B, Wang F, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer 2019; 18(1): 40.
[http://dx.doi.org/10.1186/s12943-019-0959-5] [PMID: 30866952]
[18]
Noly PE, Haddad F, Arthur-Ataam J, et al. The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload. J Thorac Cardiovasc Surg 2017; 154(6): 2070-9.
[http://dx.doi.org/10.1016/j.jtcvs.2017.05.102] [PMID: 28712579]
[19]
Kivelä R, Hemanthakumar KA, Vaparanta K, et al. Endothelial cells regulate physiological cardiomyocyte growth via VEGFR2-mediated paracrine signaling. Circulation 2019; 139(22): 2570-84.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036099] [PMID: 30922063]
[20]
Guo J, Mihic A, Wu J, et al. Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy. Eur Heart J 2015; 36(37): 2530-40.
[http://dx.doi.org/10.1093/eurheartj/ehv294] [PMID: 26160001]
[21]
Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7(1): 1535750.
[http://dx.doi.org/10.1080/20013078.2018.1535750] [PMID: 30637094]
[22]
Wang Y, Zhao R, Liu D, et al. Exosomes derived from miR-214-enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting CaMKII. Oxid Med Cell Longev 2018; 2018: 4971261.
[http://dx.doi.org/10.1155/2018/4971261] [PMID: 30159114]
[23]
Melo SF, Fernandes T, Baraúna VG, et al. Expression of MicroRNA-29 and collagen in cardiac muscle after swimming training in myocardial-infarcted rats. Cell Physiol Biochem 2014; 33(3): 657-69.
[http://dx.doi.org/10.1159/000358642] [PMID: 24642957]
[24]
Huang Y, Tang S, Huang C, et al. Circulating miRNA29 family expression levels in patients with essential hypertension as potential markers for left ventricular hypertrophy. Clin Exp Hypertens 2017; 39(2): 119-25.
[http://dx.doi.org/10.1080/10641963.2016.1226889] [PMID: 28287884]
[25]
Li M, Wang N, Zhang J, et al. MicroRNA-29a-3p attenuates ET-1-induced hypertrophic responses in H9c2 cardiomyocytes. Gene 2016; 585(1): 44-50.
[http://dx.doi.org/10.1016/j.gene.2016.03.015] [PMID: 26992639]
[26]
Chen L, Xiao H, Wang ZH, et al. miR-29a suppresses growth and invasion of gastric cancer cells in vitro by targeting VEGF-A. BMB Rep 2014; 47(1): 39-44.
[http://dx.doi.org/10.5483/BMBRep.2014.47.1.079] [PMID: 24209632]
[27]
Chang KT, Wang LH, Lin YM, Cheng CF, Wang GS. CELF1 promotes vascular endothelial growth factor degradation resulting in impaired microvasculature in heart failure. FASEB 2021; 35(5): e21512.
[http://dx.doi.org/10.1096/fj.202002553R]

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