Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice
Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice
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DOI：
10.1152/ajpheart.01264.2008
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Aasum, Ellen
中科院分区：
文献类型：
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作者：
Boardman, Neoma;Hafstad, Anne D.;Aasum, Ellen
Boardman N，Hafstad AD，Larsen TS，Severson DL，Aasum E.增加了2型糖尿病小鼠心脏基础代谢和兴奋-收缩偶联的氧成本。Am J Physiol心脏圈Physiol 296：H第1373-H1379,2009。2009年3月13日首次出版；DOI：10.1152/ajpheart.01264.2008。-我们之前已经报道，2型糖尿病(db/db)小鼠的心脏表现出心脏效率下降，这是由于独立于工作的心肌氧消耗增加(与Doto(2)相比，无负荷M(V))，这表明更多的O-2用于非机械过程，如基础代谢(M(V)比Doto(2bm))和兴奋-收缩偶联(M(V)比Doto(2ECC))。虽然心脏新陈代谢和/或钙离子处理的改变可能导致糖尿病心脏能量消耗的增加，但这些单独过程的氧耗的直接测量尚未确定。在这项研究中，我们1)验证了一种在Doto(2)上直接(M(V)在Doto(2无负载)上)和M(V)在Doto(2bm)上和M(V)在Doto(2ECC)上分别在离体灌流小鼠心脏上测定无负荷M(V)的方法，2)确定了db/db小鼠心脏这些过程的O-2成本。根据心脏做功(以压力-体积面积(PVA)测量)和M(V)与DOTO(2)之间的关系推算出的无负荷M(V)高于DOTO(2)，发现与直接在无负荷逆行灌流心脏(M(V)高于DOTO(2))中测量的M(V)相对应。K+阻断心脏M(V)over Doto(2)定义为M(V)over Doto(2bm)，M(V)over Doto(2bm)与M(V)over Doto(2bm)之差代表M(V)over Doto(2bm)。通过证明灌流液脂肪酸(FA)和/或钙离子浓度的升高导致M(V)比Doto(2bm)和/或M(V)比Doto(2ECC)的变化来验证这一过程。Db/db小鼠M(V)高于Doto(2bm)是由于M(V)高于Doto(2bm)，M(V)高于Doto(2ECC)。葡萄糖和胰岛素的升高减少了FA的氧化，减少了M(V)而不是DOTO(2 Bm)和M(V)。总之，这项研究提供了直接证据，证明糖尿病患者的M(V)高于Doto(2bm)和M(V)高于Doto(2ECC)，而且由于M(V)高于Doto(2)的降低效应，急性代谢干预可能对糖尿病心脏有治疗益处。
Boardman N, Hafstad AD, Larsen TS, Severson DL, Aasum E. Increased O-2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice. Am J Physiol Heart Circ Physiol 296: H1373-H1379, 2009. First published March 13, 2009; doi:10.1152/ajpheart.01264.2008.-We have reported previously that hearts from type 2 diabetic (db/db) mice show decreased cardiac efficiency due to increased work-independent myocardial O-2 consumption (unloaded M(V) over dotO(2)), indicating higher O-2 use for nonmechanical processes such as basal metabolism (M(V) over dotO(2BM)) and excitation-contraction coupling (M(V) over dotO(2ECC)). Although alterations in cardiac metabolism and/or Ca2(+) handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O-2 cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded M(V) over dotO(2) directly (M(V) over dotO(2unloaded)) and for determining M(V) over dotO(2BM) and M(V) over dotO(2ECC) separately in isolated perfused mouse hearts and 2) determine O-2 cost for these processes in hearts from db/db mice. Unloaded M(V) over dotO(2), extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and M(V) over dotO(2), was found to correspond with M(V) over dotO(2) measured directly in unloaded retrograde perfused hearts (M(V) over dotO(2unloaded)). M(V) over dotO(2) in K+-arrested hearts was defined as M(V) over dotO(2BM); the difference between M(V) over dotO(2unloaded) and M(V) over dotO(2BM) represented M(V) over dotO(2ECC). This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca2+ concentrations resulted in changes in either M(V) over dotO(2BM) and/or M(V) over dotO(2ECC). The higher M(V) over dotO(2unloaded) in db/db mice was due to both a higher M(V) over dotO(2BM) and M(V) over dotO(2ECC). Elevation of glucose and insulin decreased FA oxidation and reduced both M(V) over dotO(2unloaded) and M(V) over dotO(2BM). In conclusion, this study provides direct evidence that M(V) over dotO(2BM) and M(V) over dotO(2ECC) are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a M(V) over dotO(2)-lowering effect.