Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Sci Rep. 2019 Sep 4;9(1):12741. doi: 10.1038/s41598-019-49231-9.
Constitutive expression of the chemokine Mcp1 in mouse cardiomyocytes creates a model of inflammatory cardiomyopathy, with death from heart failure at age 7-8 months. A critical pathogenic role has previously been proposed for induced oxidative stress, involving NADPH oxidase activation. To test this idea, we exposed the mice to elevated oxygen levels. Against expectation, this prevented, rather than accelerated, the ultrastructural and functional signs of heart failure. This result suggests that the immune signaling initiated by Mcp1 leads instead to the inhibition of cellular oxygen usage, for which mitochondrial respiration is an obvious target. To address this hypothesis, we combined the Mcp1 model with xenotopic expression of the alternative oxidase (AOX), which provides a sink for electrons blocked from passage to oxygen via respiratory complexes III and IV. Ubiquitous AOX expression provided only a minor delay to cardiac functional deterioration and did not prevent the induction of markers of cardiac and metabolic remodeling considered a hallmark of the model. Moreover, cardiomyocyte-specific AOX expression resulted in exacerbation of Mcp1-induced heart failure, and failed to rescue a second cardiomyopathy model directly involving loss of cIV. Our findings imply that mitochondrial involvement in the pathology of inflammatory cardiomyopathy is multifaceted and complex.
组成型表达趋化因子 Mcp1 于小鼠心肌细胞中可建立炎症性心肌病模型，在 7-8 月龄时死于心力衰竭。先前曾提出诱导性氧化应激具有关键的致病作用，涉及 NADPH 氧化酶的激活。为了验证这一观点，我们将小鼠暴露于高氧环境中。出乎意料的是，这并没有加速，反而阻止了心力衰竭的超微结构和功能迹象。这一结果表明，Mcp1 引发的免疫信号转而导致细胞对氧气使用的抑制，而线粒体呼吸显然是这一过程的靶标。为了验证这一假设，我们将 Mcp1 模型与异种表达交替氧化酶（AOX）相结合，后者为通过呼吸复合物 III 和 IV 阻断传递到氧气的电子提供了一个汇。普遍表达 AOX 仅略微延迟了心脏功能恶化的发生，并且不能阻止被认为是该模型标志的心脏和代谢重构标志物的诱导。此外，心肌细胞特异性 AOX 的表达导致 Mcp1 诱导的心力衰竭恶化，并且未能挽救第二个直接涉及 cIV 缺失的心肌病模型。我们的研究结果表明，线粒体参与炎症性心肌病的病理过程是多方面且复杂的。
