Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.
Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.
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DOI：
10.1016/j.yjmcc.2018.06.007
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发表时间：
2018-08
影响因子：
5
通讯作者：
Brookes PS
中科院分区：
文献类型：
--
作者：
Nadtochiy SM;Wang YT;Nehrke K;Munger J;Brookes PS
细胞溶质NAD+依赖性脱乙酰酶SIRT 1的刺激对缺血-再灌注（IR）损伤具有心脏保护作用。NAD+前体包括烟酰胺单甘肽（NMN）被认为通过SIRT 1诱导心脏保护。在此，虽然NMN保护灌注心脏免受IR（功能恢复：NMN 42±7%相对于媒介物11±3%），但这种保护对SIRT 1抑制剂斯普利特霉素不敏感（恢复47±8%）。虽然NMN诱导的心脏保护作用在Sirt 3 −/−心脏中不存在（恢复率为9±5%），但这可能是由于Sirt 3 −/−的基线损伤增强（恢复率为6±2%），因为WT心脏中类似的损伤水平也减弱了NMN的保护作用。考虑到NMN的替代心脏效应，以及NAD+糖酵解的需求，我们假设NMN可能通过直接刺激心脏糖酵解部分提供保护。在原代心肌细胞中，NMN诱导细胞溶质和细胞外酸化和乳酸升高。此外，[U-13 C]葡萄糖示踪在完整的心脏显示，NMN刺激糖酵解通量。与糖酵解在NMN诱导的保护中的作用一致，在没有葡萄糖（棕榈酸酯作为燃料源）的情况下灌注的心脏或用半乳糖（没有来自糖酵解的ATP）灌注的心脏没有表现出NMN的益处（恢复分别为11±4%和15±2%）。已知早期再灌注期间的酸中毒具有心脏保护作用（即，酸后处理），并且我们还发现，当在再灌注时急性递送NMN时，NMN具有心脏保护作用（恢复39±8%）。NMN的这种作用与酸中毒无关，提示机制重叠。我们得出结论，NMN的急性心脏保护作用部分是通过糖酵解刺激介导的，其下游保护机制涉及缺血期间增强的ATP合成和/或再灌注期间增强的酸中毒。
Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42±7% vs. vehicle 11±3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47±8%). Although NMN-induced cardioprotection was absent in Sirt3−/− hearts (recovery 9±5%), this was likely due to enhanced baseline injury in Sirt3−/− (recovery 6±2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN. Considering alternative cardiac effects of NMN, and the requirement of glycolysis for NAD+, we hypothesized NMN may confer protection in part via direct stimulation of cardiac glycolysis. In primary cardiomyocytes, NMN induced cytosolic and extracellular acidification and elevated lactate. In addition, [U-13C]glucose tracing in intact hearts revealed that NMN stimulated glycolytic flux. Consistent with a role for glycolysis in NMN-induced protection, hearts perfused without glucose (palmitate as fuel source), or hearts perfused with galactose (no ATP from glycolysis) exhibited no benefit from NMN (recovery 11±4% and 15±2% respectively). Acidosis during early reperfusion is known to be cardioprotective (i.e., acid post-conditioning), and we also found that NMN was cardioprotective when delivered acutely at reperfusion (recovery 39±8%). This effect of NMN was not additive with acidosis, suggesting overlapping mechanisms. We conclude that the acute cardioprotective benefits of NMN are mediated in part via glycolytic stimulation, with the downstream protective mechanism involving enhanced ATP synthesis during ischemia and/or enhanced acidosis during reperfusion.
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影响因子：
20.1
作者：
Rane S;He M;Sayed D;Vashistha H;Malhotra A;Sadoshima J;Vatner DE;Vatner SF;Abdellatif M
通讯作者：
Abdellatif M
影响因子：
5
作者：
Nadtochiy SM;Urciuoli W;Zhang J;Schafer X;Munger J;Brookes PS
通讯作者：
Brookes PS
影响因子：
--
作者：
ALLARD, MF;SCHONEKESS, BO;LOPASCHUK, GD
通讯作者：
LOPASCHUK, GD
DOI：
10.1152/ajpheart.00587.2011
发表时间：
2011-10-01
影响因子：
4.8
作者：
Nadtochiy, Sergiy M.;Yao, Hongwei;Brookes, Paul S.
通讯作者：
Brookes, Paul S.
影响因子：
2.9
作者：
NICOLLI, A;PETRONILLI, V;BERNARDI, P
通讯作者：
BERNARDI, P