Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways
Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways
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DOI：
10.1152/ajpheart.00932.2010
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发表时间：
2011-01-01
影响因子：
4.8
通讯作者：
Kypson, Alan P.
中科院分区：
文献类型：
--
作者：
Anderson, Ethan J.;Rodriguez, Evelio;Kypson, Alan P.
安德森EJ，罗德里格斯E，安德森CA，Thayne K，奇特伍德WR，Kypson AP。糖尿病患者心脏中细胞死亡倾向的增加是由细胞依赖性途径介导的。美国生理学杂志心脏循环生理学300：H118-H124，2011年。首次发表于2010年11月12日; doi：10.1152/ajpheart.00932.2010。-在实验模型中，进行性能量缺乏和心肌细胞数量减少是导致心力衰竭的两个突出因素。介导心肌细胞死亡的信号被认为来自外部（例如，细胞因子）和内源性（e.例如，在一个实施例中，线粒体）来源，但支持这些机制的证据仍不清楚，在人类中几乎不存在。在这项研究中，我们研究了线粒体通透性转换孔（mPTP）对钙（Ca 2+）的敏感性，使用透化的右心房肌纤维，从糖尿病（n = 9）和非糖尿病（n = 12）患者的冠状动脉疾病接受非紧急冠状动脉血运重建术。在模拟体内心脏能量状态（丙酮酸、谷氨酸、苹果酸和100 μ M ADP）的条件下，糖尿病患者的心脏线粒体对Ca 2+诱导的mPTP开放的敏感性比非糖尿病患者增加。糖尿病心脏线粒体中mPTP Ca 2+敏感性的增加伴随着在相同条件下线粒体H2 O2排放速率的显著增加，尽管在这些条件下呼吸能力或线粒体酶含量没有差异。糖尿病心房组织中内源性凋亡途径介体caspase-9的活性更高，而外源性途径介体caspase-8的活性在两组之间无变化。此外，caspase-3活性在糖尿病心房组织中没有显著增加。这些数据共同表明，糖尿病患者的心肌具有更大的线粒体依赖性细胞死亡的总体倾向，可能是由于线粒体内发生的代谢应激引起的变化，使它们更容易受到损伤，如Ca 2+过载。此外，他们进一步支持了线粒体代表未来治疗的可行靶点的观点，这些治疗旨在改善心力衰竭和其他糖尿病合并症。
Anderson EJ, Rodriguez E, Anderson CA, Thayne K, Chitwood WR, Kypson AP. Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am J Physiol Heart Circ Physiol 300: H118-H124, 2011. First published November 12, 2010; doi:10.1152/ajpheart.00932.2010.-Progressive energy deficiency and loss of cardiomyocyte numbers are two prominent factors that lead to heart failure in experimental models. Signals that mediate cardiomyocyte cell death have been suggested to come from both extrinsic (e.g., cytokines) and intrinsic (e. g., mitochondria) sources, but the evidence supporting these mechanisms remains unclear, and virtually nonexistent in humans. In this study, we investigated the sensitivity of the mitochondrial permeability transition pore (mPTP) to calcium (Ca2+) using permeabilized myofibers of right atrium obtained from diabetic (n = 9) and nondiabetic (n = 12) patients with coronary artery disease undergoing nonemergent coronary revascularization surgery. Under conditions that mimic the energetic state of the heart in vivo (pyruvate, glutamate, malate, and 100 mu M ADP), cardiac mitochondria from diabetic patients show an increased sensitivity to Ca2+-induced mPTP opening compared with nondiabetic patients. This increased mPTP Ca2+ sensitivity in diabetic heart mitochondria is accompanied by a substantially greater rate of mitochondrial H2O2 emission under identical conditions, despite no differences in respiratory capacity under these conditions or mitochondrial enzyme content. Activity of the intrinsic apoptosis pathway mediator caspase-9 was greater in diabetic atrial tissue, whereas activity of the extrinsic pathway mediator caspase-8 was unchanged between groups. Furthermore, caspase-3 activity was not significantly increased in diabetic atrial tissue. These data collectively suggest that the myocardium in diabetic patients has a greater overall propensity for mitochondrial-dependent cell death, possibly as a result of metabolic stress-imposed changes that have occurred within the mitochondria, rendering them more susceptible to insults such as Ca2+ overload. In addition, they lend further support to the notion that mitochondria represent a viable target for future therapies directed at ameliorating heart failure and other comorbidities that come with diabetes.