Abstract
Cardiovascular diseases (CVDs) are among the top leading causes of mortality worldwide. Besides canonical environmental and genetic changes reported so far for CVDs, non-coding RNAs (ncRNAs) have emerged as key regulators of genetic and epigenetic mechanisms involved in CVD progression. High-throughput and sequencing data revealed that almost 80% of the total genome not only encodes for canonical ncRNAs, such as micro and long ncRNAs (miRNAs and lncRNAs), but also generates novel non-canonical sub-classes of ncRNAs, such as isomiRs and miRNA- and lncRNA-like RNAs. Moreover, recent studies reveal that canonical ncRNA sequences can influence the onset and evolution of CVD through novel “non-canonical” mechanisms. However, a debate exists over the real existence of these non-canonical ncRNAs and their concrete biochemical functions, with most of the dark genome being considered as “junk RNA”. In this review, we report on the ncRNAs with a scientifically validated canonical and non-canonical biogenesis. Moreover, we report on canonical ncRNAs that play a role in CVD through non-canonical mechanisms of action.
Highlights
According to the World Health Organization (WHO), cardiovascular, respiratory, and neonatal conditions are the top global leading causes of death, causing 55% of total deaths worldwide [1]
The biogenesis is an additional criterion to divide all small non-coding RNA (ncRNA) into seven subclasses [36,38,39], such as snRNAs, ribosomal RNAs (rRNAs), snoRNAs, transfer RNAs (tRNAs), micro RNAs (miRNAs), small Cajal body-specific RNAs, and intron-derived ncRNAs [36,38,39]
First data reporting the existence of tRNA-derived miRNAs emerged from HIV infected cells showing an increased number of tRNAs of approximatively 20 nt in length deriving from the HIV-transcriptional promoter tRNA-Lys3 [58,60]
Summary
According to the World Health Organization (WHO), cardiovascular, respiratory, and neonatal conditions are the top global leading causes of death, causing 55% of total deaths worldwide [1]. If we exclude the coronavirus (COVID-19) pandemic disease, which accounted for almost 10% of total deaths worldwide in 2020 [2], cardiovascular diseases (CVDs), such as ischaemic heart disease, stroke, hypertension, and atherosclerosis, are among the top leading causes of morbidity and mortality, causing almost 21% of all deaths globally [3,4]. In addition to the canonical genetic changes, non-canonical epigenetic modifications strongly influence cardiovascular disorders. ECs exposed to disturbed flow show an activated or so-called “maladapted” phenotype, characterized by a pro-inflammatory and pro-apoptotic state [21], partly balanced by a flow-mediated increase in EC proliferation [16,17,19]. The growth of advanced lesions leads to a critical reduction of arterial lumen and blood flow, reduced oxygen supply, and rupture or erosion of the plaques, which can cause thrombosis [29]
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