Mainali Nirjal, Balasubramaniam Meenakshisundaram, Pahal Sonu, Griffin W Sue T, Shmookler Reis Robert J, Ayyadevara Srinivas
Bioinformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, 72205, USA.
Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
Basic Res Cardiol. 2025 May 7. doi: 10.1007/s00395-025-01109-w.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated. We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways. In this study, we further investigate the molecular mechanisms altered by induced MI in mice, which were also implicated by proteomics of postmortem human hippocampal aggregates from Alzheimer's disease (AD) and cardiovascular disease (CVD) patients, vs. age-matched controls (AMC). We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes). We used leave-one-out analysis (LOOA) to determine the contribution of each protein to overall aggregate cohesion, and gene ontology meta-analyses of constituent proteins to define critical organelles, processes, and pathways that distinguish AD and/or CVD from AMC aggregates. We identified influential proteins in both AD and CVD aggregates, many of which are associated with pathways or processes previously implicated in neurodegeneration such as mitochondrial, oxidative, and endoplasmic-reticulum stress; protein aggregation and proteostasis; the ubiquitin proteasome system and autophagy; axonal transport; and synapses.
心血管疾病（CVDs）是全球主要的死亡原因。已知CVD会增加后续神经退行性变的风险，但其中涉及的机制和蛋白质尚未阐明。我们之前表明，在小鼠中诱导心肌梗死（MI）并与假手术MI小鼠相比，会导致蛋白质聚集增加、心脏和大脑中的内质网（ER）应激以及蛋白质稳态途径的变化。在本研究中，我们进一步研究了诱导MI在小鼠中改变的分子机制，这些机制在阿尔茨海默病（AD）和心血管疾病（CVD）患者与年龄匹配对照（AMC）的死后人类海马聚集体蛋白质组学中也有涉及。我们利用聚集体内交联来识别蛋白质 - 蛋白质接触或接近度，从而重建聚集体“接触组”（非功能性相互作用组）。我们使用留一法分析（LOOA）来确定每种蛋白质对整体聚集体凝聚力的贡献，并对组成蛋白质进行基因本体元分析，以定义区分AD和/或CVD与AMC聚集体的关键细胞器、过程和途径。我们在AD和CVD聚集体中鉴定出有影响力的蛋白质，其中许多与先前涉及神经退行性变的途径或过程相关，如线粒体、氧化和内质网应激；蛋白质聚集和蛋白质稳态；泛素蛋白酶体系统和自噬；轴突运输；以及突触。
