SERCA1 expression enhances the metabolic efficiency of improved contractility in post-ischemic heart.
SERCA1 expression enhances the metabolic efficiency of improved contractility in post-ischemic heart.
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DOI：
10.1016/j.yjmcc.2009.08.031
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发表时间：
2009-11
影响因子：
5
通讯作者：
Lewandowski, E. Douglas
中科院分区：
文献类型：
--
作者：
O'Donnell, J. Michael;Pound, Kayla;Xu, Xianyao;Lewandowski, E. Douglas
心肌昏迷的特征是线粒体三羧酸（TCA）循环和氧消耗保持正常，尽管收缩性降低，但代谢与功能解耦。最近有报道称心脏肌内质网Ca2+- atp酶（SERCA1）的过度表达可减少再灌注功能障碍。在这项研究中，我们确定SERCA治疗是否能改善代谢与功能的耦合。将携带SERCA1 cDNA的PBS（对照）或腺病毒通过冠状动脉灌注注入Sprague-Dawley大鼠心脏。基因转移3天后，取离体心脏灌注0.4 mM [2,4,6,8,10,12,14,16- 13c8]棕榈酸酯和5 mM葡萄糖，缺血15 min，再灌注40 min。与心肌休克一致，PBS组心率压积（RPP）和左心室发育压（LVDP）下降30-40% （p<0.05）。SERCA1过表达组dP/dt比对照组高20% (p<0.05)， LVDP和RPP恢复到缺血前水平。从动态13C NMR来看，两组再灌注时的TCA循环通量与缺血前值相似。因此，SERCA1治疗可以恢复心脏功与TCA循环通量之间的耦合效率。SERCA1也提高了氧化效率，因为与PBS组相比，胞质内NADH转运到线粒体的量显著增加。此外，磷酸肌酸与ATP的比值（PCr/ATP）没有受到SERCA1表达的影响，尽管功能增强，而且PBS组在40分钟再灌注时抑制的脂肪酸氧化没有被SERCA1逆转。这些数据表明，SERCA1处理显著改善了代谢偶联和NADH转运。
Myocardial stunning is characterized by a metabolic uncoupling from function as mitochondrial tricarboxylic acid (TCA) cycle and oxygen consumption remain normal despite reduced contractility. Overexpression of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA1) in hearts has recently been reported to reduce dysfunction at reperfusion. In this study we determine whether the metabolic coupling to function improves with SERCA treatment. PBS (control) or adenovirus carrying the cDNA for SERCA1 were delivered via coronary perfusion in vivo to Sprague-Dawley rat hearts. Three days following gene transfer, isolated hearts were perfused with 0.4 mM [2,4,6,8,10,12,14,16-13C8] palmitate and 5 mM glucose, and subjected to 15 min ischemia followed by 40 min reperfusion. Consistent with myocardial stunning, rate-pressure-product (RPP) and left ventricular developed pressure (LVDP) were depressed 30-40% (p<0.05) in the PBS group. With SERCA1 overexpression, dP/dt was 20% greater than controls (p<0.05), and LVDP and RPP recovered to preischemic values. From dynamic 13C NMR, TCA cycle flux at reperfusion was similar to preischemic values for both groups. Therefore, the efficiency of coupling between cardiac work and TCA cycle flux was restored with SERCA1 treatment. Oxidative efficiency was also enhanced with SERCA1 as cytosolic NADH transport into the mitochondria was significantly greater compared to the PBS group. In addition, the phosphocreatine to ATP ratio (PCr/ATP) was not compromised with SERCA1 expression, despite enhanced function, and depressed fatty acid oxidation at 40 min reperfusion in the PBS group was not reversed with SERCA1. These data demonstrate metabolic coupling and NADH transport are significantly improved with SERCA1 treatment.
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影响因子：
37.8
作者：
del Monte, F;Williams, E;Hajjar, RJ
通讯作者：
Hajjar, RJ
影响因子：
5
作者：
O'Donnell, J. Michael;Fields, Aaron D.;Lewandowski, E. Douglas
通讯作者：
Lewandowski, E. Douglas
DOI：
10.1152/ajpheart.01113.2003
发表时间：
2004-06-01
影响因子：
4.8
作者：
O'Donnell, JM;Kudej, RK;Lewandowski, ED
通讯作者：
Lewandowski, ED
DOI：
10.1152/ajpheart.00663.2007
发表时间：
2007-10-01
影响因子：
4.8
作者：
Talukder, M. A. Hassan;Kalyanasundaram, Anuradha;Zweier, Jay L.
通讯作者：
Zweier, Jay L.
影响因子：
3.4
作者：
O'Donnell, JM;Alpert, NM;Lewandowski, ED
通讯作者：
Lewandowski, ED