Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection.
Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection.
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生长因子介导的缺血诱导的心脏保护衰老功能障碍的逆转。
DOI：
10.1152/ajpheart.00470.2005
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Edelberg,JayM
中科院分区：
文献类型：
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作者：
Zheng,Jingang;Chin,Andrew;Duignan,Inga;Won,Kyung-Heon;Hong,MunK;Edelberg,JayM
基于肿瘤坏死因子-α（TNF-α）在缺血预处理（IPC）中的作用以及TNF-α诱导的血小板源性生长因子-AB（PDGF-AB）介导的心脏保护作用和IPC介导的心脏保护作用的年龄相关性丧失，我们假设靶向基于PDGF-AB的途径将恢复IPC在衰老心脏中的心脏保护作用。为了研究这一点，在4月龄和24月龄的F344大鼠中诱导IPC。与对照组相比，IPC后1天分离的年轻心脏切片显示TNF-α增加。在老年大鼠中，TNF-α在基线时高于IPC年轻大鼠，并且在IPC后没有显著改变。在IPC时，用PDGF-AB与血管内皮生长因子和血管生成素-2（一种称为PVA的组合）治疗老年大鼠，而不是单独使用PDGF-AB，可降低TNF-α。此外，与年轻心脏相比，IPC在老年心脏中诱导了更大的细胞凋亡，PVA处理可减少细胞凋亡，但PDGF-AB处理可显着增加细胞凋亡。为了测试这些发现的意义，在IPC后1天对另外的大鼠进行永久性冠状动脉结扎。IPC对幼鼠心肌有保护作用[心肌梗死后14天，左室短轴缩短率为29 ± 6%，对照组为17 ± 4%，P < 0.05; Masson三色染色心肌梗死面积为13 ± 2%，对照组为17 ± 4%;P< 0.05]。然而，在老年大鼠中，IPC降低了MI后14天的存活率（33% vs.对照组67%;P< 0.05）。用PVA而不是单独的PDGF-AB治疗IPC衰老大鼠，逆转了IPC诱导的死亡率（PVA-IPC-MI存活率，88%; PDGF-AB-IPC-MI，14%）和心肌损伤减少（缩短分数：PVA-IPC，31 ± 1% vs.对照MI，21 ± 6%，P < 0.05; MI尺寸：PVA-IPC，12 ± 2%对比对照MI，18 ± 3%LVA，P< 0.05），因此证明基于PDGF-AB的途径可以逆转IPC介导的心脏保护中的衰老损伤。
Based on the role of tumor necrosis factor-α (TNF-α) in ischemic preconditioning (IPC) and the age-associated loss of both TNF-α-induced platelet-derived growth factor-AB (PDGF-AB)-mediated cardioprotection and IPC-mediated cardioprotection, we hypothesized that targeting of PDGF-AB-based pathways would restore cardioprotection by IPC in the aging heart. To study this, IPC was induced in 4- and 24-mo-old F344 rats. Sections of young hearts isolated 1 day post-IPC revealed increased TNF-α compared with controls. In old rats, TNF-α was higher at baseline than IPC young rats and was not significantly altered after IPC. Treatment of old rats with PDGF-AB with vascular endothelial growth factor and angiopoietin-2 (a combination termed PVA), but not PDGF-AB alone, at the time of IPC decreased TNF-α. In addition, when compared with young hearts, IPC induced greater apoptosis in the old hearts, which was decreased with PVA treatment but was markedly increased with PDGF-AB. To test the significance of these findings, additional rats underwent permanent coronary ligation 1 day post-IPC. IPC was cardioprotective in young rats [14 days postmyocardial infarction (MI), fractional shortening 29 ± 6% vs. control MI 17 ± 4%,P< 0.05; Masson’s trichrome stain MI size: 13 ± 2% vs. control MI 17 ± 4% left ventricular area (LVA);P< 0.05]. In old rats, however, IPC reduced the post-MI 14-day survival (33% vs. controls 67%;P< 0.05). Treatment of IPC-aging rats with PVA, but not PDGF-AB-alone, reversed IPC-induced mortality (PVA-IPC-MI survival, 88%; PDGF-AB-IPC-MI, 14%) and reduced myocardial injury (fractional shortening: PVA-IPC, 31 ± 1% vs. control MI, 21 ± 6%,P< 0.05; MI size: PVA-IPC, 12 ± 2% vs. control MI, 18 ± 3% LVA,P< 0.05) and thus demonstrated that PDGF-AB-based pathways can reverse the senescent impairment in IPC-mediated cardioprotection.