Alternative Splicing in Cardiovascular Disease—A Survey of Recent Findings

Abstract

Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.

Dysregulated RNA processing and metabolism: a new hallmark of ageing and provocation for cellular senescence

“…Interestingly, changes in splicing factor expression and the consequent downstream effects on splicing are not a feature of ageing in naked mole-rats, a species with exceptionally long life and negligible senescence [59]. Disrupted patterns of alternative splicing are a major characteristic of many common chronic age-related diseases, such as cancer [60], neurodegenerative disease [61], osteoarthritis and cardiovascular disease [62], and also more systemic diseases of the elderly, such as frailty and sarcopenia [63]. Most of these diseases are also characterised by senescence as described above.…”

Post-Transcriptional Modification by Alternative Splicing and Pathogenic Splicing Variants in Cardiovascular Development and Congenital Heart Defects

“…New sequencing technologies, such as single-cell RNA seq and Nanopore sequencing, have already been implemented in neuroscience and cancer biology [27][28][29], and more recently in cardiovascular disease [30], revealing cell-type specific alternative splicing events and their functional impacts on cell behavior and fate. Considering that impaired splicing can lead to various human diseases [31][32][33][34][35][36], efforts tailored to baseline understanding of tissue-specific and cell-specific alternative splicing processes and their physiologic roles are essential to fully reveal their contribution to human disease.…”

Myocardin regulates exon usage in smooth muscle cells through induction of splicing regulatory factors

“…Transcriptomic diversity is further increased by alternative internal promoters and transcription start sites, and such events may be more common than AS [ 17 ]. That AS is widespread and plays critical roles in human disease is clear [ 18 , 19 ], but the magnitude of its proteomic impact has been questioned [ 20 ]. This suggests that studies aiming to assess tissue specific AS should also aim to probe its proteomic consequences.…”