Abstract
Cardiovascular disease is the leading cause of death amongst diabetic individuals. Atherosclerosis is the prominent driver of diabetic vascular complications, which is triggered by the detrimental effects of hyperglycemia and oxidative stress on the vasculature. Research has extensively shown diabetes to result in the malfunction of the endothelium, the main component of blood vessels, causing severe vascular complications. The pathogenic mechanism in which diabetes induces vascular dysfunction, however, remains largely unclear. Alternative splicing of protein coding pre-mRNAs is an essential regulatory mechanism of gene expression and is accepted to be intertwined with cellular physiology. Recently, a role for alternative splicing has arisen within vascular health, with aberrant mis-splicing having a critical role in disease development, including in atherosclerosis. This review focuses on the current knowledge of alternative splicing and the roles of alternatively spliced isoforms within the vasculature, with a particular focus on disease states. Furthermore, we explore the recent elucidation of the alternatively spliced QKI gene within vascular cell physiology and the onset of diabetic vasculopathy. Potential therapeutic strategies to restore aberrant splicing are also discussed.
Highlights
Alternative splicing, the removal of introns followed by specific exon ligation prior to mRNA translation, allows for a single gene to coordinate the synthesis of a multitude of protein isoforms, all of which can vary in both their structural and functional characteristics
Alternative splicing is an extensive source of diversity for both coding and non-coding RNAs; diversity that is greatly needed to achieve the higher degree of complexity, regarding gene expression, observed in humans
Aberrant alternative splicing has been shown to have oligonucelotides as therapeutics, including spliceosome-mediated RNA trans-splicing (SMaRT) technologies, antisense critical roleoligonucleotides in the pathogeneiss of numerous diseases, the design and development o (ASOs) and bifunctional oligonucleotides, has attracted significant attention due to their ability to be designed to bind to a complementary sequence and trigger either the activation or inhibition of splicing events by sterically herapeutics able to mitigate mis-splicing has emerged as a popular area of research
Summary
Alternative splicing, the removal of introns followed by specific exon ligation prior to mRNA translation, allows for a single gene to coordinate the synthesis of a multitude of protein isoforms, all of which can vary in both their structural and functional characteristics. Atherosclerosis refers to the process of atherogenesis, the build-up of plaques on the inner lining of arterial walls [15] These plaques, composed of substances found within the blood such as fat, cholesterol, and calcium, can harden overtime resulting in the narrowing of arteries and the restriction of blood flow. Glycaemic control can reduce the onset of complications, the correlation between diabetes and cardiovascular disease remains a significant health and economic burden globally [17], suggesting that well managed glycaemic control alone is not enough to solely prevent the onset of endothelial cell dysfunction and atherosclerosis development. Due to the extensive involvement of endothelial cell dysfunction in cardiovascular disease onset amongst individuals with diabetes, the ability to repair and regenerate the endothelium may offer a more effective therapeutic approach towards vascular complications for these individuals. Potential therapeutic avenues with promise to mitigate mis-splicing and restore the disease phenotype are evaluated
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