Multi-omics in thoracic aortic aneurysm: the complex road to the simplification

Abstract

Background Thoracic aortic aneurysm (TAA) is a serious condition that affects the aorta, characterized by the dilation of its first segment. The causes of TAA (e.g., age, hypertension, genetic syndromes) are heterogeneous and contribute to the weakening of the aortic wall. This complexity makes treating this life-threatening aortopathy challenging, as there are currently no etiological therapy available, and pharmacological strategies, aimed at avoiding surgical aortic replacement, are merely palliative. Recent studies on novel therapies for TAA have focused on identifying biological targets and etiological mechanisms of the disease by using advanced -omics techniques, including epigenomics, transcriptomics, proteomics, and metabolomics approaches. Methods This review presents the latest findings from -omics approaches and underscores the importance of integrating multi-omics data to gain more comprehensive understanding of TAA. Results Literature suggests that the alterations in TAA mediators frequently involve members of pro-fibrotic process (i.e., TGF-β signaling pathways) or proteins associated with cell/extracellular structures (e.g., aggrecans). Further analyses often reported the importance in TAA of processes as inflammation (PCR, CD3, leukotriene compounds), oxidative stress (chromatin OXPHOS, fatty acids), mitochondrial respiration and glycolysis/gluconeogenesis (e.g., PPARs and HIF1a). Of note, more recent metabolomics studies added novel molecular markers to the list of TAA-specific detrimental mediators (proteoglycans). Conclusion It is increasingly clear that integrating data from different -omics branches, along with clinical data, is essential as well as complicated both to reveal hidden relevant information and to address complex diseases such as TAA. Importantly, recent progresses in metabolomics highlighted novel potential and unprecedented marks in TAA diagnosis and therapy.

The key role of miRNA in syndromic and sporadic forms of ascending aortic aneurysms as biomarkers and targets of novel therapeutic strategies

“…Currently, the technological progresses and the reduction of their costs have allowed deep investigations of the pathogenetic mechanisms of many diseases, including aneurysms, for developing newest generation treatments ( Lareyre et al, 2023 ; Rega et al, 2023 ). In particular, the researchers are applying integrative multi-omics which appear to be necessary and show the potential to provide a greater quantity of information, ranging from the original causes of disease to the functional consequences or relevant interactions, and to clarify the physiological and pathophysiological role of miRNAs ( Lareyre et al, 2023 ; Rega et al, 2023 ).…”

“…Both analyses constitute a very serious challenge ( Recanatini and Menestrina, 2023 ), because firstly the interactions cannot be causal, since most links must be estimated through correlations or co-expressions; second, it is necessary to explore interactions between thousands or millions of entities (e.g., genes, epigenetic factors, proteins, metabolites, etc.) and this requires a huge amount of computational resources ( Lareyre et al, 2023 ; Rega et al, 2023 ). Regarding machine learning analysis, the first issue is data harmonization and dimensionality ( Lareyre et al, 2023 ; Rega et al, 2023 ).…”

“…In recent years, many studies have investigated the role of epigenetic modulation in regulating the pathogenetic mechanism of all types of aneurysms ( Chakraborty et al, 2023 ; Han et al, 2023 ; Rega et al, 2023 ; Tao et al, 2023 ). The regulation of gene expression appears to be quite interesting, especially considering the complex pathophysiological mechanisms underlying the sporadic forms of aortic aneurysms ( Balistreri, 2015 ; Pisano et al, 2017 ; Saeyeldin et al, 2019 ), which are the result of a close interaction between genetic and modifiable lifestyle factors (e.g., diet, smoking, infections, drug use, alcohol, sedentary lifestyle, etc.)…”

“…Epigenetic mechanisms regulate gene expression without changing the DNA sequence ( Jiang et al, 2020 ; Wei et al, 2020 ; Lareyre et al, 2023 ). The latter include DNA methylation, post-translational histone modifications, and noncoding RNA ( Jiang et al, 2020 ; Wei et al, 2020 ; Han et al, 2023 ; Lareyre et al, 2023 ; Rega et al, 2023 ). In recent years, many studies have investigated the role of epigenetic mechanisms in ATAA pathophysiology ( Chakraborty et al, 2023 ; Han et al, 2023 ; Rega et al, 2023 ; Tao et al, 2023 ).…”

The causal relationship between thoracic aortic aneurysm and immune cells: a mendelian randomization study

“…The most severe manifestation of TAA is aortic dissection or rupture, yet a significant number of patients remain asymptomatic [ 1 ]. The recognized causes include syphilis infection, autoimmune diseases (such as arthritis), connective tissue disorders (such as Marfan syndrome, Loeys Dietz syndrome, and Ehlers-Danlos syndrome), vascular degeneration (linked to factors like smoking and hypertension), and the presence of a bicuspid aortic valve [ 2 ]. At present, antihypertensive medications stand as the sole effective palliative treatment for TAA, while surgical replacement of the dilated aorta remains the only proven treatment strategy [ 3 ].…”