Hypoxia-inducible factor-1 improves inotropic responses of cardiac myocytes in ageing heart without affecting mitochondrial activity
Hypoxia-inducible factor-1 improves inotropic responses of cardiac myocytes in ageing heart without affecting mitochondrial activity
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DOI：
10.1113/expphysiol.2009.051649
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发表时间：
2010-06-01
影响因子：
2.7
通讯作者：
Weiss, Harvey R.
中科院分区：
文献类型：
--
作者：
Tan, Tao;Marin-Garcia, Jose;Weiss, Harvey R.
衰老降低了心肌细胞对正性肌力药物的反应能力。我们假设，缺氧诱导因子-1（HIF-1）将改善功能和Ca 2+瞬态反应的老化心肌细胞的正性肌力药物，这将采取行动，在一定程度上，通过改变线粒体活性。使用年轻（3-4个月）和年长的Fischer 344大鼠（18-20个月）。缺氧诱导因子-1 α上调环吡酮胺（CPX，50毫克公斤-1 2天）。Western blot检测缺氧诱导因子-1上调。心肌细胞收缩和Ca 2+瞬变测量基线和后毛喉素和哇巴因。我们还测量了线粒体复合体的活动和活性氧（ROS）的产生。在年轻组中，毛喉素（31%）和哇巴因（31%）显着增加缩短百分比。在年轻+ CPX组中观察到类似的变化。钙瞬变也以类似的方式响应。然而，在老年组中，毛喉素（12%）和哇巴因（6%）并未显着增加肌细胞收缩力或Ca 2+瞬变。在老年+ CPX组中，毛喉素（34%）和哇巴因（29%）的作用恢复。在年轻+ CPX组中，与年轻组相比，ROS产生和线粒体复合物I和III活性增加。在老年组中没有观察到这些差异。这些数据表明，受损的功能和Ca 2+作用的正性肌力药物在老年心肌细胞。HIF-1的上调恢复了这种钝化的反应，但这与HIF-1诱导的线粒体活性改变无关。因此，我们发现HIF-1改善老年心肌细胞的变力性，而不需要线粒体活性的变化。
Ageing reduces the ability of cardiac myocytes to respond to inotropic agents. We hypothesized that hypoxia-inducible factor-1 (HIF-1) would improve the functional and Ca2+ transient responses of ageing myocytes to the inotropic agents and this would act, in part, through altered mitochondrial activity. Young (3-4 months) and older Fischer 344 rats (18-20 months) were used. Hypoxia-inducible factor-1 alpha was upregulated with ciclopirox olamine (CPX, 50 mg kg-1 on 2 days). Hypoxia-inducible factor-1 upregulation was detected by Western blot. Cardiomyocyte contraction and Ca2+ transients were measured at baseline and after forskolin and ouabain. We also measured mitochondrial complex activities and production of reactive oxygen species (ROS). In the young group, forskolin (31%) and ouabain (31%) significantly increased percentage shortening. Similar changes were observed in the young + CPX group. Calcium transients also responded in a similar manner. However, in the older group, forskolin (12%) and ouabain (6%) did not significantly increase myocyte contractility or Ca2+ transients. In the older + CPX group, the effects of forskolin (34%) and ouabain (29%) were restored. In the young + CPX group, there was increased ROS production and mitochondrial complex I and III activity compared with the young group. These differences were not observed in older groups. These data demonstrate an impaired functional and Ca2+ effect of positive inotropic agents in older myocytes. Upregulation of HIF-1 restored this blunted response, but this was not related to changed mitochondrial activity induced by HIF-1. Thus, we found that HIF-1 improved inotropy in older myocytes without requiring mitochondrial activity changes.