Long Non-Coding Rnas: Crucial Players of Cardiomyocyte Apoptosis
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Chen X, Liu Z, Li Z, Gao J, Yu Z, Li P, Htet Aung LH. Long Non-Coding RNAs: Crucial Players of Cardiomyocyte Apoptosis. J Cardiol and Cardiovasc Sciences. 2019;3(5):1-9 Review Article Open Access Long Non-Coding RNAs: Crucial Players of Cardiomyocyte Apoptosis Xiatian Chen1,2, Ziqian Liu1,2, Zhe Li1,2, Jinning Gao1,2, Zhongjie Yu1,2, Peifeng Li1*, Lynn Htet Htet Aung1# 1Center for Molecular Genetics, Institute for Translational Medicine, Qingdao University, Qingdao, 266000, Shandong, China 2School of Basic Medicine, Qingdao University, Qingdao, 266000, Shandong, China Article Info Abstract Article Notes Long non-coding RNAs (lncRNAs) have gained more attention in recent Received: September 1, 2019 years as a potential new regulator of nearly all biological regulation. LncRNAs Accepted: October 25, 2019 are over 200 nucleotides in length, and it can interact with other non-coding *Correspondence: RNAs or specific proteins to influence the gene expression. Cardiomyocyte *Dr. Peifeng Li, Center for Molecular Genetics, Institute for apoptosis is associated with cardiovascular diseases. Accumulating studies Translational Medicine, Qingdao University, #38 Dengzhou Road, have uncovered novel lncRNAs-mediated regulation of cardiovascular diseases; Qingdao, 266000, Shandong, China; Email: peifl[email protected]. however, the knowledge of the mechanisms by how to act is still limited. This #Dr. Lynn Htet Htet Aung, Center for Molecular Genetics, review highlights the role of lncRNAs involved in cardiomyocyte apoptosis with Institute for Translational Medicine, Qingdao University, #38 a focus on the regulatory axis. These examples may provide helpful insights on Dengzhou Road, Qingdao, 266000, Shandong, China; Email: how lncRNAs interfere with cardiomyocyte apoptosis. [email protected]. © 2019 Li P, Htet Aung LH. This article is distributed under the terms of the Creative Commons Attribution 4.0 International Introduction License. Heart diseases remain the worldwide leading cause of morbidity and mortality, and the occurrence of this disease is closely related to the apoptosis of cardiomyocytes1,2. In recent years, the number of new patients has been increasing due to factors such as environment, living standards and family heredity, and there are still no effective drugs to cure. In the human genome, almost 98% of the genome does not encode for protein, only about 2% of genes encode protein3 in length, although they don’t take part in the protein-coding, some studies .show LncRNAs they are play defined a vital as beingrole inlonger some than biology 200 nucleotides processes, like X chromosome inactivation, cell cycle regulation, cellular differentiation4,5. Because cardiomyocytes are nonregenerative, so cardiomyocyte apoptosis is critical to the normal functioning of the heart. Emerging evidence suggests that lncRNAs may act as endogenous sponge RNAs to interact with microRNAs (miRNAs) has been proved to play a necessary role in the regulation of cardiomyocyteand influence the apoptosis expression (Figure of miRNAs1A). target genes. This model and their functions in modulating cardiomyocyte apoptosis, it may In this review, we have summarized recently identified lncRNAs provideThe Classical significant Pathways information of Cardiomyocyte for diagnosis and Apoptosis therapy. Cell survival and death are vital for organ development, tissue deathhomeostasis, program and and body kill themselvesdevelopment. in aThe controlled death procedure way; this ofprogress cells is isstarted known since as programmedthe date of production. cell death; The this cells word activate was coinedan intracellular in 1965 by R.lockshin and C.williams in the study of silkworms. In 1972, Kerr Page 1 of 9 Chen X, Liu Z, Li Z, Gao J, Yu Z, Li P, Htet Aung LH. Long Non-Coding RNAs: Crucial Journal of Cardiology and Cardiovascular Players of Cardiomyocyte Apoptosis. J Cardiol and Cardiovasc Sciences. 2019;3(5):1-9 Sciences Figure 1. The overview of lncRNAs in cardiomyocyte apoptosis. (A) LncRNAs interact with miRNAs to modulate cardiomyocyte apoptosis. lncRNA, long noncoding RNA; miRNA, microRNA. (B) Classical pathway of cardiomyocyte apoptosis. TNF, tumor necrosis factors; FasL, Fas ligand; TRADD, TNFR- associated death domain; FADD, Fas-associated death domain (FADD); Casp, Caspase; Apaf-1, apoptosis protease- activating factors. One-way arrows indicate downstream activation. Two-way arrows indicate interaction. which is released by macrophages and Fas ligand is a cell munity6. Biologists often use the terms andprogrammed colleagues cell firstly death introduced and apoptosis the concept interchangeably. of “apoptosis” active natural killer cells, bind to their individual death toProgrammed the scientific cell com death is developmental progress that surface protein produced by cytotoxic T lymphocytes and usually proceeds by apoptosis. Apoptosis is also the mode of cell death occurring in a variety of other settings and deathreceptors. domain The (FADD)cytoplasmic cohesion tail of proteins death receptors and then recruits recruit has roles in normal homeostasis, inhibition of cancer, and TNFR- associated death domain (TRADD) or Fas-associated disease processes. (DISC) that activates downstream related caspase, to cause apoptosiscaspase-8 (Figureand caspase-10 1 B). to form a death-induced complex Apoptosis depends on proteolytic enzymes called Genomic Contexts of Long Non-Coding RNAs 7,8 to help kill the cell Long non-coding RNAs (lncRNAs) are generally changescaspases, during which apoptosis cleave specificare the fragmentationintracellular proteinsof DNA . The most important biochemical distinguished from other noncoding RNAs because of phospholipids and the loss of membrane potential in in the nucleus, the extroversion of plasma membrane Due to the lack of technology and cognition, noncoding mitochondria, and the release of cytochrome c into their length and are ranging from 200 -10000 nucleotides.9-11. But still have some early pioneers had the foresight to realize that itgene was space not entirelywas termed useless “junk”12. In for 1961, a long Jacob time and Monod intrinsiccytoplasmic apoptosis solutes. pathway Apoptosis also is known executed as mitochondrial through two different pathways, named “intrinsic” and “extrinsic”. The control of apoptosis, and it is triggered by intracellular repressor-operator model of gene regulation13. In 1969, firstBritten deduced and Davidsonthe existence hypothesized of mRNA anda model speculated of gene the signals when cells are stressed, such as oxidative stress, stresses can lead to changes in the permeability of 14. Some thecalcium mitochondrial overload andouter DNA membrane damage (Figureand the 1B).release These of expression regulation in eukaryotes, in which noncoding RNAs act as a mediator affecting gene expression c can activate the apoptosis protease-activating factors functionallyof the first cases described to uncover15-17. the lncRNAs function of gene- (Apaf-1),cytochrome which c into assemble the cytoplasmic into apoptosome matrix. and Cytochrome activates specific control in the 1990s. Xist is the first lncRNA to be caspase 9. Caspase 9 cleavages and activates downstream Own to the development of high through sequencing, caspase protein to cause cell apoptosis (Figure 1B). such as microarray and RNA-sequencing, more and more lncRNAs have been found to play an essential role in gene By contrast, the extrinsic pathway is initiated by the extracellular ligands binding to cell-surface death (Figureregulation. 2). There are many explanations for the role of receptors: tumor necrosis factors-α (TNF-α) receptors, Fas lncRNA in gene expression, mainly in the following points and TRAIL receptors. For instance, tumor necrosis factor, Page 2 of 9 Chen X, Liu Z, Li Z, Gao J, Yu Z, Li P, Htet Aung LH. Long Non-Coding RNAs: Crucial Journal of Cardiology and Cardiovascular Players of Cardiomyocyte Apoptosis. J Cardiol and Cardiovasc Sciences. 2019;3(5):1-9 Sciences Figure 2. The function of lncRNAs in gene expression. The orange block represents the promoter, blue blocks represent the sense genes. The long black lines represent gene sequences. 1. LncRNAs may be as stand-alone transcription units Wang and colleagues have demonstrated that the located in noncoding promoter space, can negatively lncRNA CARL (cardiac apoptosis-related lncRNA) was an inhibitor of cardiomyocyte apoptosis19. CARL acts as or through inducing the chromatin remodeling or positively affect downstream gene expression, 18. the sponge for miR-539 and regulates the expression of and histone modification to interfere with gene bymiR-539, impairing which miR-539-dependent can provoke mitochondrial PHB2 downregulation. fission and 2. LncRNAsexpression can form complementary double strands apoptosis via PHB2. Therefore, CARL can inhibit apoptosis with transcripts of protein-coding genes, interfere (necrosis-related factor) as an endogenous sponger RNA with mRNA splicing, and form different splicing forLater, miR-873. they NRFidentified directly another binds to lncRNA,miR-873 andnamed regulates NRF forms. 3. LncRNAs can also form complementary double Moreover, they found the lncRNA MDRL (Mitochondrial20 strands with transcripts of protein-coding genes dynamic-relatedRIPK1/RIPK3 expression lncRNA) andcould programmed inhibit mitochondrial cell death and produce endogenous siRNA under the action of the Dicer enzyme. in turn relieves inhibition of miR-484 processing by miR- 361fission21. and apoptosis by downregulating miR-361, which the activity of