Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury.
Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury.
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FAM3D 在心肌缺血再灌注损伤中的心脏保护和抗炎作用。
DOI：
10.1161/circresaha.123.322640
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发表时间：
2023
影响因子：
20.1
通讯作者：
Silverman,Mic
中科院分区：
文献类型：
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作者：
Rhee,James;Freeman,Rebecca;Roh,Kangsan;Lyons,Margaret;Xiao,Chunyang;Zlotoff,Daniel;Yeri,Ashish;Li,Haobo;Guerra,Justin;Guseh,JSawalla;Kuznetsov,Alexandra;Houstis,Nicholas;Roh,Jason;Damilano,Federico;Liu,Xiaojun;Silverman,Mic
心肌缺血-再灌注损伤后不良心脏重构的病理生理机制尚不完全清楚。虽然心肌梗死（MI）时的大梗死面积和功能受损是最终心力衰竭的强有力预测因素，但即使是最初功能保留的患者也可能发生导致心力衰竭的晚期不良重塑。1在此，我们对入选OMEGAREMODEL试验2的急性ST段抬高型心肌梗死患者亚组进行了血浆蛋白质组学研究，这些患者经直接经皮冠状动脉介入治疗成功再灌注。MI后不良或有利的心脏重构定义为MI后2 - 4周至6个月通过心脏磁共振成像（MRI）评估的左心室收缩末期容积指数分别增加或减少20%。我们选择了11名不良和10名良好的重塑者，他们在初始左心室质量、功能和梗死面积方面相匹配，并且具有相似的人口统计学和临床特征。使用1.3 K SomaS-can平台分析初始MRI时采集的血浆样本。火山图（图[A]）显示了14种候选分子（绿色点），其在有利和不利重塑之间的丰度差异满足显著性（未调整P< 0.05）和倍数变化（> 1.4）的阈值。细胞因子FAM 3D（具有序列相似性3D的家族）在有利的重塑者中升高，并表现出最高的总体倍数变化。这种分泌因子结合主要在中性粒细胞和单核细胞上表达的甲酰肽受体，并调节其运输。3 FAM 3D的ELISA与SomaScan测量结果密切相关，并证实了两组之间的差异（图[B]）。基于我们的人类发现，我们观察了成年小鼠左前降支冠状动脉结扎30分钟后的FAM 3D（或Oit 1），随后进行了不同时间的再灌注。再灌注8小时后的血浆FAM 3D水平与肌钙蛋白-I水平相关（图[B]）。再灌注后24小时的全面器官收获显示，脾脏可能是循环FAM 3D增加的来源（图[C]），这与显示缺血心肌和造血组织之间串扰的先前研究一致，4尽管蛋白质差异未达到统计学显著性。
Pathophysiological mechanisms underlying adverse cardiac remodeling after myocardial ischemia-reperfusion injury are incompletely understood. Although large infarct size and impaired function at the time of myocardial infarction (MI) are strong predictors of eventual heart failure, even patients with initially preserved function can experience late adverse remodeling that leads to heart failure. 1 Here, we performed plasma proteomics in a subgroup of patients enrolled in the OMEGAREMODEL trial2 presenting with acute ST-elevation MI and successfully reperfused with primary percutaneous coronary intervention. Adverse or favorable cardiac remodeling after MI was defined as a 20% increase or decrease, respectively, in left ventricular end-systolic volume index from 2 to 4 weeks to 6 months after MI as assessed by cardiac magnetic resonance imaging (MRI). We selected 11 adverse and 10 favorable remodelers who were matched for initial left ventricular mass, function, and infarct size, and shared similar demographic and clinical characteristics. Plasma samples taken at the time of the initial MRI were analyzed with the 1.3 K SomaS-can platform. The volcano plot (Figure [A]) shows the 14 candidate molecules (green dots) whose difference in abundance between favorable and adverse remodelers satisfied threshold values for significance (unadjusted P< 0.05) and fold change (> 1.4). The cytokine FAM3D (Family with sequence similarity 3D) was elevated in favorable remodelers and exhibited the highest overall fold change. This secreted factor binds to formyl-peptide receptors expressed predominantly on neutrophils and monocytes, and regulates their trafficking. 3 ELISA for FAM3D closely correlated with SomaScan measurements and confirmed the difference between the 2 groups (Figure [B]).Based on our human findings, we looked at FAM3D (or Oit1) in adult mice after 30 minutes of left anterior descending coronary artery ligation followed by various periods of reperfusion. Plasma FAM3D levels after 8 hours of reperfusion correlated with troponin-I levels (Figure [B]). Comprehensive organ harvest 24 hours after reperfusion revealed the spleen as a likely source of increased circulating FAM3D (Figure [C]), consistent with prior studies showing cross-talk between ischemic myocardium and hematopoietic tissues, 4 although the difference in protein did not reach statistical significance.