Ronan George, Yang Jun, Zorlutuna Pinar
Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN, 46556, USA.
Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, 46556, USA.
bioRxiv. 2024 Dec 12:2024.12.06.627231. doi: 10.1101/2024.12.06.627231.
Aging is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and numerous other diseases, but the mechanisms of these aging-related effects remain elusive. Chronic changes in the microenvironment and paracrine signaling behaviors have been implicated, but remain understudied. Here, for the first time, we directly compare extracellular vesicles obtained from young and aged patients to identify therapeutic or disease-associated agents, and directly compare vesicles isolated from heart tissue matrix (TEVs) or plasma (PEVs). While young EVs showed notable overlap of miRNA cargo, aged EVs differed substantially, indicating differential age-related changes between TEVs and PEVs. TEVs overall were uniquely enriched in miRNAs which directly or indirectly demonstrate cardioprotective effects, with 45 potential therapeutic agents implicated in our analysis. Both populations also showed increased predisposition to disease with aging, though through different mechanisms. PEVs were largely correlated with chronic systemic inflammation, while TEVs were more related to cardiac homeostasis and local inflammation. From this, 17 protein targets unique to TEVs were implicated as aging-related changes which likely contribute to the development of cardiovascular disease.
衰老是心血管疾病的主要风险因素，心血管疾病是全球主要死因，也是许多其他疾病的主要风险因素，但这些与衰老相关的影响机制仍不清楚。微环境和旁分泌信号行为的慢性变化已被认为与之相关，但仍未得到充分研究。在此，我们首次直接比较从年轻和老年患者获得的细胞外囊泡，以确定治疗或疾病相关因子，并直接比较从心脏组织基质（TEV）或血浆（PEV）中分离的囊泡。虽然年轻的细胞外囊泡显示出微小RNA（miRNA）含量有显著重叠，但老年的细胞外囊泡差异很大，表明TEV和PEV之间存在与年龄相关的差异变化。总体而言，TEV在直接或间接显示心脏保护作用的miRNA中独特富集，我们的分析涉及45种潜在治疗因子。随着衰老，这两种群体也都表现出对疾病的易感性增加，尽管机制不同。PEV在很大程度上与慢性全身炎症相关，而TEV则更多地与心脏内环境稳态和局部炎症相关。据此，17种TEV特有的蛋白质靶点被认为是与衰老相关的变化，这可能导致心血管疾病的发生。
