The ischemia-enhanced myocardial infarction protection-related lncRNA protects against acute myocardial infarction

Abstract

Long non-coding RNA RP11-64B16.4 (myocardial infarction protection-related lncRNA [MIPRL]) is among the most abundant and the most upregulated lncRNAs in ischemic human hearts. However, its role in ischemic heart disease is unknown. We found MIPRL was conserved between human and mouse and its expression was increased in mouse hearts after acute myocardial infarction (AMI) and in cultured human and mouse cardiomyocytes after hypoxia. The infarcted size, cardiac cell apoptosis, cardiac dysfunction, and cardiac fibrosis were aggravated in MIPRL knockout mice after AMI. The above adverse results could be reversed by re-expression of MIPRL via adenovirus expressing MIPRL. Both in vitro and in vivo, we identified that heat shock protein beta-8 (HSPB8) was a target gene of MIPRL, which was involved in MIPRL-mediated anti-apoptotic effects on cardiomyocytes. We further discovered that MIPRL could combine with the messenger RNA (mRNA) of HSPB8 and increase its expression in cardiomyocytes by enhancing the stability of HSPB8 mRNA. In summary, we have found for the first time that the ischemia-enhanced lncRNA MIPRL protects against AMI via its target gene HSPB8. MIPRL might be a novel promising therapeutic target for ischemic heart diseases such as AMI.

Keywords

acute myocardial infarction / apoptosis / cardiomyocyte / long noncoding RNA / MIPRL

References

1	PL Laforgia, C Auguadro, S Bronzato, A Durante. The reduction of mortality in acute myocardial infarction: from bed rest to future directions. Int J Prev Med. 2022;8:56. 13.
2	JL Anderson, DA Morrow. Acute myocardial infarction. N Engl J Med. 2017;376:2053-2064.
3	M Tibaut, D Mekis, D Petrovic. Pathophysiology of myocardial infarction and acute management strategies. Cardiovasc Hematol Agents Med Chem. 2017;14:150-159.
4	F Crea, P Libby. Acute coronary syndromes: the way forward from mechanisms to precision treatment. Circulation. 2017;136:1155-1166.
5	LE Philippen, E Dirkx, PA da Costa-Martins, LJ De Windt. Non-coding RNA in control of gene regulatory programs in cardiac development and disease. J Mol Cell Cardiol. 2015;89:51-58.
6	RP Juni, KC t Hart, RH Houtkooper, et al. Long noncoding RNAs in cardiometabolic disorders. FEBS Lett. 2022;596:1367-1387.
7	LA Saddic, MI Sigurdsson, TW Chang, et al. The long noncoding RNA landscape of the ischemic human left ventricle. Circ Cardiovasc Genet. 2017;10:e001534.
8	Z Ward, S Schmeier, L Saddic, et al. Novel and annotated long noncoding RNAs associated with ischemia in the human heart. Int J Mol Sci. 2021;22:11324.
9	F Sievers, A Wilm, D Dineen, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega. Mol Syst Biol. 2011;7:539.
10	AM Lodrini, MJ Goumans. Cardiomyocytes cellular phenotypes after myocardial infarction. Front Cardiovasc Med. 2021;8:750510.
11	JM Bravo-San Pedro, G Kroemer, L Galluzzi. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812-1824.
12	HF Deng, J Zou, N Wang, et al. Nicorandil alleviates cardiac remodeling and dysfunction post-infarction by up-regulating the nucleolin/autophagy axis. Cell Signal. 2022;92:110272.
13	H Qiu, P Lizano, L Laure, et al. H11 kinase/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac overload. Circulation. 2011;124:406-415.
14	W Wu, L Lai, M Xie, et al. Insights of heat shock protein 22 in the cardiac protection against ischemic oxidative stress. Redox Biol. 2020;34:101555.
15	X Sui, D Li, H Qiu, et al. Activation of the bone morphogenetic protein receptor by H11kinase/Hsp22 promotes cardiac cell growth and survival. Circ Res. 2009;104:887-895.
16	EV Mymrikov, AS Seit-Nebi, NB Gusev. Large potentials of small heat shock proteins. Physiol Rev. 2011;91:1123-1159.
17	VE Villegas, PG Zaphiropoulos. Neighboring gene regulation by antisense long non-coding RNAs. Int J Mol Sci. 2015;16:3251-3266.
18	D Vu?i?evi?, H Schrewe, UA Orom. Molecular mechanisms of long ncRNAs in neurological disorders. Front Genet. 2014;5:48.
19	O Harismendy, D Notani, X Song, et al. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature. 2011;470:264-268.
20	P Puthanveetil, S Chen, B Feng, et al. Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med. 2015;19:1418-1425.
21	K Wang, CY Liu, LY Zhou, et al. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun. 2015;6:6779.
22	MA Faghihi, C Wahlestedt. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol. 2009;10:637-643.
23	Z Liao, Y Chen, C Duan, et al. Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics. 2021;11:268-291.
24	Y Song, C Zhang, J Zhang, et al. Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction. Theranostics. 2019;9:2346-2360.
25	A Farokhian, A Rajabi, A Sheida, et al. Apoptosis and myocardial infarction: role of ncRNAs and exosomal ncRNAs. Epigenomics. 2023;15:307-334.
26	H Liu, S Liu, X Qiu, et al. Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells. Autophagy. 2020;16:2140-2155.
27	X Liu, ZD Xiao, L Han, et al. lncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat Cell Biol. 2016;18:431-442.
28	KC Wang, YW Yang, B Liu, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120-124.
29	S Uchida, S Dimmeler. Long noncoding RNAs in cardiovascular diseases. Circ Res. 2015;116:737-750.
30	Y Yu, LL Hu, L Liu, et al. Hsp22 ameliorates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidative stress, and apoptosis. Bioengineered. 2021;12:12544-12554.
31	L Yu, Q Liang, W Zhang, et al. HSP22 suppresses diabetes-induced endothelial injury by inhibiting mitochondrial reactive oxygen species formation. Redox Biol. 2019;21:101095.
32	MD Gober, CC Smith, K Ueda, et al. Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. J Biol Chem. 2003;278:37600-37609.
33	P Rusmini, R Cristofani, M Galbiati, et al. The role of the heat shock protein B8 (HSPB8) in motoneuron diseases. Front Mol Neurosci. 2017;10:176.
34	L Gonzalez-Malerva, J Park, L Zou, et al. High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci USA. 2011;108:2058-2063.
35	J Stebbing, A Filipovic, LC Lit, et al. LMTK3 is implicated in endocrine resistance via multiple signaling pathways. Oncogene. 2013;32:3371-3380.
36	J Cheng, M Ji, H Jing, et al. DUSP12 ameliorates myocardial ischemia-reperfusion injury through HSPB8-induced mitophagy. J Biochem Mol Toxicol. 2023;37:e23310.
37	E Ehler, T Moore-Morris, S Lange. Isolation and culture of neonatal mouse cardiomyocytes. J Vis Exp. 2013;6:50154.
38	SG Zimmerman, NC Peters, AE Altaras, et al. Optimized RNA ISH, RNA FISH and protein-RNA double labeling (IF/FISH) in Drosophila ovaries. Nat Protoc. 2013;8:2158-2179.
39	M Ratnadiwakara, ML ?nk?. mRNA stability assay using transcription inhibition by actinomycin D in mouse pluripotent stem cells. Bio Protoc. 2018;8:e3072.
40	M Torres, D Becquet, S Guillen, et al. RNA pull-down procedure to identify RNA targets of a long non-coding RNA. J Vis Exp. 2018;134:57379.