Aging Alters the Aortic Proteome in Health and Thoracic Aortic Aneurysm

Abstract

Background: Aging enhances most chronic diseases but its impact on human aortic tissue in health and in thoracic aortic aneurysms (TAA) remains unclear. Methods: We employed a human aortic biorepository of healthy specimens (n=17) and those that underwent surgical repair for TAA (n=20). First, we performed proteomics comparing aortas of healthy donors to aneurysmal specimens, in young (ie, <60 years of age) and old (ie, ≥60 years of age) subjects. Second, we measured proteins, via immunoblotting, involved in mitophagy (ie, Parkin) and also mitochondrial-induced inflammatory pathways, specifically TLR (toll-like receptor) 9, STING (stimulator of interferon genes), and IFN (interferon)-β. Results: Proteomics revealed that aging transformed the aorta both quantitatively and qualitatively from health to TAA. Whereas young aortas exhibited an enrichment of immunologic processes, older aortas exhibited an enrichment of metabolic processes. Immunoblotting revealed that the expression of Parkin directly correlated to subject age in health but inversely to subject age in TAA. In TAA, but not in health, phosphorylation of STING and the expression of IFN-β was impacted by aging regardless of whether subjects had bicuspid or tricuspid valves. In subjects with bicuspid valves and TAAs, TLR9 expression positively correlated with subject age. Interestingly, whereas phosphorylation of STING was inversely correlated with subject age, IFN-β positively correlated with subject age. Conclusions: Aging transforms the human aortic proteome from health to TAA, leading to a differential regulation of biological processes. Our results suggest that the development of therapies to mitigate vascular diseases including TAA may need to be modified depending on subject age.

The Endothelial Transcription Factor ERG Mediates a Differential Role in the Aneurysmatic Ascending Aorta with Bicuspid or Tricuspid Aorta Valve: A Preliminary Study

“…Probably, a synergistic action of all these elements reflects the different AAA phenotypes associated with BAV, as stressed in our works, than those detected in TAV individuals [4,10,12]. Differently, TAV subjects show a more advanced age of AAA onset, about versus the 70-75 years, and a pathogenesis more related to vascular aging and the resultant remodeling and degeneration process associated with a preeminent fibrosis, that significantly reduces the probability of AAA progression in dissection and rupture [2,[13][14][15][16][17]. Precisely, a typical vascular remodeling and degeneration, accompanied by wound healing associated with a significant increase of circulating EPC levels [9,11], tissue expression of TGF-β and Smad-3 [18][19][20][21] consequent inflammation, endothelial-to-mesenchymal transition (EndMT) [22][23][24] and fibrosis [25], embody aorta dilation, or better, AAA disease, in TAV patients.…”

Vascular Aging and Vascular Disease Have Much in Common!

“…There are strong risk factors for TAA, including genetic determinants, such as the Marfan syndrome and bicuspid aortic valves, as well as hemodynamic determinants, such as hypertension and inflammatory diseases of the aorta. [5][6][7] The article by Tyrrell et al 4 reports on proteomic comparisons between 4 cohorts of patients: healthy young and healthy elderly individuals and young and older patients with TAA. This allows a unique dissection of the distinct impact of age and disease.…”

“…22 Disease states, such as atherosclerosis and diabetes, are known to counterregulate antioxidant mechanisms, 34,37,38 and, together with altered mitochondrial and immune function, this can lead to an overall increase in inflammation in the vessel. 36,39 Increased inflammation has been linked to atherosclerotic plaque rupture 40 and aortic aneurysms, 36,41 and, indeed, Tyrrell et al 4 found differences in protein expression in aged patients with TAA, reflecting changes in mitochondrial function and repair, as well as reactive oxygen species pathways.…”

“…Tyrrell et al 4 investigated potential connections between vascular age and thoracic aortic aneurysm (TAA)—an age-related vascular disease that often results in death caused by aortic rupture. There are strong risk factors for TAA, including genetic determinants, such as the Marfan syndrome and bicuspid aortic valves, as well as hemodynamic determinants, such as hypertension and inflammatory diseases of the aorta.…”

“…In most cardiovascular disease-targeted clinical trials, elderly patients are excluded despite the fact that age-related mortality and morbidity are largely driven by cardiovascular diseases. [1][2][3] In this issue of ATVB, Tyrrell et al 4 present elegant and important work that sheds light on the close relationship between vascular aging and vascular diseases.…”