Role of noncoding RNAs in cardiac ageing

Abstract

The global population is estimated to reach 9.8 billion by 2050, of which 2.1 billion will comprise individuals above 60 years of age. As the number of elderly is estimated to double from 2017, it is a victory of the modern healthcare system but also worrisome as ageing, and the onset of chronic disease are correlated. Among other chronic conditions, cardiovascular diseases (CVDs) are the leading cause of death in the aged population. While the underlying cause of the age-associated development of CVDs is not fully understood, studies indicate the role of non-coding RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lnc-RNAs) in the development of age-associated CVDs. miRNAs and lnc-RNAs are non-coding RNAs which control gene expression at the post-transcriptional level. The expression of specific miRNAs and lnc-RNAs are reportedly dysregulated with age, leading to cardiovascular system changes and ultimately causing CVDs. Since miRNAs and lnc-RNAs play several vital roles in maintaining the normal functioning of the cardiovascular system, they are also being explored for their therapeutic potential as a treatment for CVDs. This review will first explore the pathophysiological changes associated with ageing. Next, we will review the known mechanisms underlying the development of CVD in ageing with a specific focus on miRNA and lnc-RNAs. Finally, we will discuss the therapeutic options and future challenges towards healthy cardiac ageing. With the global ageing population on the rise, this review will provide a fundamental understanding of some of the underlying molecular mechanisms of cardiac ageing.

Keywords: cardiac ageing; cardiovascular disease; long non-coding RNA; microRNA; molecular changes; non-coding RNA.

Figure 1

Summary of the molecular changes that occur in the aged heart such as telomere shortening (A), epigenetic changes (B), mitochondrial dysfunction (C), neurohormonal changes (D) dysregulation of non-coding RNAs (E), and cellular senescence (F). mtDNA, mitochondrial DNA; ROS, reactive oxygen species; miRNA, microRNA; lncRNA, long non-coding RNA; AngII, angiotensin II; IGF, insulin like growth factor; RyR, ryanodine receptor; MyBP-C, f Apoptosis of cardiomyocytes, loss of pacemaker cells, thickening and calcification of the valves, and impairment of vascular structure and function.

Figure 2

Summary of miRNA biogenesis via canonical and non-canonical pathway. Canonical pathway: (A) The miRNA gene is transcribed by RNA polymerase II to form a primary mi-RNA (pri-miRNA). (B) The pri-miRNA is cleaved by Drosha and Di-George syndrome critical region 8 (DGCR8) to form the precursor miRNA (pre-miRNA). (C) Pre-miRNA is transported to the cytoplasm by exportin-5. (D) In the cytoplasm, pre-miRNA is cleaved by Dicer to form a duplex mature miRNA. (E) The mature miRNA is loaded to RNA-induced silencing complex (RISC), leading to the cleavage of the passenger strand. (F) miR-RISC binds to the target mRNA leading to its degradation. Non-canonical pathway: (G) Synthesis of miRNA by Drosha/DGCR8 independent pathway: The primary miRNA is spliced by a spliceosome, forming a branched pre-miRNA. The pre-miRNA is debranched by a debranching enzyme, after which the synthesis is similar to the canonical pathway. (H) Synthesis of miRNA by Dicer-independent pathway: The pre-miRNA formed by the cleavage of pri-miRNA by Drosha/DGCR8 is exported to the cytoplasm. The pre-miRNA is not long enough to be processed by Dicer and forms the RISC.

Figure 3

Summary of cardiovascular enriched miRNAs and lncRNAs that are dysregulated with ageing. PNUTS, phosphatase-1 nuclear targeting subunit; SIRT-1, sirtuin 1; TSP-1, thrombospondin-1; CTGF, connective tissue growth factor; SPRY1, sprout protein homolog 1; SPRED1, sprouty related EVH1 domain containing 1; ECM proteins, Extracellular matrix proteins.