Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, Montefiore University Hospital, 1300 Morris Park Avenue, New York, NY, 10461, USA.
Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, Montefiore University Hospital, New York, NY, 10461, USA.
Mol Med. 2024 Oct 26;30(1):188. doi: 10.1186/s10020-024-00927-3.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein crucial for cellular stress response and survival, particularly in the nervous and cardiovascular systems. Unlike traditional neurotrophic factors, MANF primarily regulates endoplasmic reticulum (ER) stress and protects cells by reducing ER stress-induced apoptosis. MANF operates both inside and outside cells, influencing key pathways like JAK/STAT and NF-κB to enhance cell survival during stress. Beyond its neuroprotective role, MANF is also vital in cardiovascular protection, mitigating damage by reducing inflammation and maintaining cellular function. Elevated MANF levels have been observed in patients experiencing myocardial infarction and murine models of ischemia-reperfusion (I/R) injury, highlighting its importance in these conditions. Overexpression of MANF in cardiomyocytes reduces ER-stress-induced cell death, while its depletion worsens this effect. Treatment with recombinant MANF (rMANF) has been shown to improve cardiac function in mice with I/R injury by decreasing infarct size and inflammation. Research also indicates that alterations in the α1-helix region of MANF can impact its structure, expression, secretion, and overall function. Given its protective effects and involvement in critical signaling pathways, MANF is being explored as a potential therapeutic target for ER stress-related diseases, including neurodegenerative disorders and cardiovascular conditions like myocardial I/R injury.
中脑星形胶质细胞衍生神经营养因子（MANF）是一种对细胞应激反应和存活至关重要的蛋白质，特别是在神经系统和心血管系统中。与传统的神经营养因子不同，MANF 主要调节内质网（ER）应激，并通过减少 ER 应激诱导的细胞凋亡来保护细胞。MANF 在细胞内外均起作用，影响 JAK/STAT 和 NF-κB 等关键途径，以增强细胞在应激期间的存活。除了其神经保护作用外，MANF 在心血管保护中也至关重要，通过减少炎症和维持细胞功能来减轻损伤。在经历心肌梗死的患者和缺血再灌注（I/R）损伤的小鼠模型中观察到 MANF 水平升高，突出了其在这些情况下的重要性。在心肌细胞中过表达 MANF 可减少 ER 应激诱导的细胞死亡，而其耗竭则会加重这种效应。用重组 MANF（rMANF）治疗已显示可通过减少梗塞面积和炎症来改善 I/R 损伤小鼠的心脏功能。研究还表明，MANF 的α1-螺旋区域的改变会影响其结构、表达、分泌和整体功能。鉴于其保护作用和参与关键信号通路，MANF 被作为与 ER 应激相关的疾病（包括神经退行性疾病和心血管疾病如心肌 I/R 损伤）的潜在治疗靶点进行研究。
