Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43
Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43
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DOI：
10.1152/ajpheart.01071.2006
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发表时间：
2007-04-01
影响因子：
4.8
通讯作者：
Schulz, Rainer
中科院分区：
文献类型：
--
作者：
Boengler, Kerstin;Konietzka, Ina;Schulz, Rainer
连接蛋白43 （Cx43）定位于左心室间隙连接和心肌细胞线粒体。基因诱导的Cx43的减少以及线粒体Cx43输入的阻断可消除缺血预处理（IP）对梗死面积（IS）的减少。随着年龄的增长，心室和心房组织匀浆中Cx43的含量降低。我们现在研究是否1)衰老小鼠心脏中线粒体Cx43含量减少，2)在体内衰老小鼠心脏中IP减少的is丢失。与幼龄（< 3月）C57Bl/6小鼠心脏相比，老年（bb0 - 13月）心肌组织Cx43含量降低，而蛋白激酶C（内皮型一氧化氮合酶的一个组成部分）的表达水平保持不变。同样，在老年小鼠左室心肌分离的线粒体中，Western blot分析表明，与年轻小鼠心脏分离的线粒体相比，Cx43含量降低了40%。在幼鼠心脏中，10分钟缺血和10分钟再灌注一个周期的IP使30分钟局部缺血和120分钟再灌注后的IS（危险面积百分比）从67.7 +/- 3.3 （n = 17）降低到34.2 +/- 6.6 （n = 5, P < 0.05）。相比之下，IP在老年小鼠心脏中失去了心脏保护作用，因为未预处理（57.5 +/- 4.0,n = 10）和预处理心脏（65.4 +/- 6.3,n = 8, P =不显著）的IS没有差异。由此可见，衰老小鼠心脏中线粒体Cx43含量降低。Cx43水平的降低可能导致与年龄相关的IP对心脏保护的丧失。
Connexin 43 ( Cx43) is localized at left ventricular ( LV) gap junctions and in cardiomyocyte mitochondria. A genetically induced reduction of Cx43 as well as blockade of mitochondrial Cx43 import abolishes the infarct size ( IS) reduction by ischemic preconditioning ( IP). With progressing age, Cx43 content in ventricular and atrial tissue homogenates is reduced. We now investigated whether or not 1) the mitochondrial Cx43 content is reduced in aged mice hearts and 2) IS reduction by IP is lost in aged mice hearts in vivo. Confirming previous results, sarcolemmal Cx43 content was reduced in aged ( > 13 mo) compared with young ( < 3 mo) C57Bl/6 mice hearts, whereas the expression levels of protein kinase C is an element of and endothelial nitric oxide synthase remained unchanged. Also in mitochondria isolated from aged mice LV myocardium, Western blot analysis indicated a 40% decrease in Cx43 content compared with mitochondria isolated from young mice hearts. In young mice hearts, IP by one cycle of 10 min ischemia and 10 min reperfusion reduced IS (% of area at risk) following 30 min regional ischemia and 120 min reperfusion from 67.7 +/- 3.3 ( n = 17) to 34.2 +/- 6.6 ( n = 5, P < 0.05). In contrast, IP's cardioprotection was lost in aged mice hearts, since IS in nonpreconditioned ( 57.5 +/- 4.0, n = 10) and preconditioned hearts ( 65.4 +/- 6.3, n = 8, P = not significant) was not different. In conclusion, mitochondrial Cx43 content is decreased in aged mouse hearts. The reduced levels of Cx43 may contribute to the age-related loss of cardioprotection by IP.