A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan.
A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan.
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DOI：
10.3389/fcvm.2022.1096887
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发表时间：
2022
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
衰老与活性氧和炎症水平的增加有关，这些炎症会扰乱蛋白质平衡和线粒体功能，并导致以后生命中整个生物体的脆弱。ARA290(西比因肽)是一种位于促红细胞生成素的心脏保护域中的11-aa非造血肽序列，通过减少炎症和纤维化来调节组织保护。与年龄相关的心脏炎症与心脏的结构和功能改变有关，包括线粒体功能障碍、蛋白平衡受损、肥厚性心脏重构和收缩功能障碍。ARA290能否改善这些与年龄相关的心脏变化和老年虚弱的严重程度？我们进行了一项综合的纵向(n=48)和横向(n=144)15个月的随机对照试验，其中18月龄的Fischer 344 x Brown挪威大鼠被随机分配到接受慢性ARA290治疗或生理盐水治疗。每隔4个月重复测量一次连续超声心动图、尾压和体重。在最后一个时间点(33个月龄)计算脆弱指数。每隔4个月采集组织，以确定炎症标志物和左心室组织重塑。在分离的左心室肌细胞中评估线粒体和心肌细胞的健康状况。建立Kaplan-Meier生存曲线。使用混合ANOVA检验和线性混合回归分析来确定年龄、治疗以及年龄-治疗交互作用的影响。慢性ARA290治疗减轻了心脏非心肌细胞/心肌细胞比例、白细胞和单核细胞、促炎细胞因子、总的核因子-κB和p-核因子-κB的年龄相关性增加。此外，ARA290治疗增加了心肌细胞的自噬流量，减少了细胞内脂褐素的积累。慢性ARA290处理后，心肌细胞线粒体通透性转运孔对氧化应激的反应脱敏。同时，ARA290显著降低了与年龄相关的血压升高，并保留了左心室射血分数。最后，ARA290保留了体重，并显著降低了生命末期整个生物体范围内的其他脆弱标记。服用ARA290可减少细胞和组织炎症，减轻心血管系统内的结构和功能变化，从而改善虚弱和保持健康寿命。
Aging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age? We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan–Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions. Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life. Administration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.
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影响因子：
4.8
作者：
Judge, S;Jang, YM;Leeuwenburgh, C
通讯作者：
Leeuwenburgh, C
影响因子：
4.6
作者：
Bruunsgaard, H;Skinhoj, P;Pedersen, BK
通讯作者：
Pedersen, BK
影响因子：
5.7
作者：
Brines, Michael;Dunne, Ann N.;Dahan, Albert
通讯作者：
Dahan, Albert
影响因子：
9.3
作者：
Cohen CD;De Blasio MJ;Lee MKS;Farrugia GE;Prakoso D;Krstevski C;Deo M;Donner DG;Kiriazis H;Flynn MC;Gaynor TL;Murphy AJ;Drummond GR;Pinto AR;Ritchie RH
通讯作者：
Ritchie RH
DOI：
10.1038/s41569-018-0064-2
发表时间：
2018-09
期刊：
Nature reviews. Cardiology
影响因子：
--
作者：
Ferrucci L;Fabbri E
通讯作者：
Fabbri E