U1046, INSERM, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
Antioxid Redox Signal. 2013 Mar 20;18(9):1009-20. doi: 10.1089/ars.2012.4534. Epub 2012 Oct 26.
Heart failure (HF) is characterized by regionalized contractile alterations resulting in loss of the transmural contractile gradient across the left ventricular free wall. We tested whether a regional alteration in mitochondrial oxidative metabolism during HF could affect myofilament function through protein kinase A (PKA) signaling.
Twelve weeks after permanent left coronary artery ligation that induced myocardial infarction (MI), subendocardial (Endo) cardiomyocytes had decreased activity of complex I and IV of the mitochondrial electron transport chain and produced twice more superoxide anions than sham Endo and subepicardial cells. This effect was associated with a reduced antioxidant activity of superoxide dismutase and Catalase only in MI Endo cells. The myofilament contractile properties (Ca(2+) sensitivity and maximal tension), evaluated in skinned cardiomyocytes, were also reduced only in MI Endo myocytes. Conversely, in MI rats treated with the antioxidant N-acetylcysteine (NAC) for 4 weeks, the generation of superoxide anions in Endo cardiomyocytes was normalized and the contractile properties of skinned cardiomyocytes restored. This effect was accompanied by improved in vivo contractility. The beneficial effects of NAC were mediated, at least, in part, through reduction of the PKA activity, which was higher in MI myofilaments, particularly, the PKA-mediated hyperphosphorylation of cardiac Troponin I.
The Transmural gradient in the mitochondrial content/activity is lost during HF and mediates reactive oxygen species-dependent contractile dysfunction.
Regionalized alterations in redox signaling affect the contractile machinery of sub-Endo myocytes through a PKA-dependent pathway that contributes to the loss of the transmural contractile gradient and impairs global contractility.
心力衰竭（HF）的特征是区域性收缩改变，导致左心室游离壁的跨壁收缩梯度丧失。我们测试了 HF 期间线粒体氧化代谢的区域性改变是否可以通过蛋白激酶 A（PKA）信号影响肌球蛋白功能。
在永久性左冠状动脉结扎导致心肌梗死（MI）后 12 周，心内膜下（Endo）心肌细胞的线粒体电子传递链复合物 I 和 IV 的活性降低，产生的超氧阴离子比假手术 Endo 和心外膜细胞多两倍。这种效应与 MI Endo 细胞中只有超氧化物歧化酶和过氧化氢酶的抗氧化活性降低有关。在肌球蛋白收缩特性（Ca(2+)敏感性和最大张力）评估中，也只有 MI Endo 肌球蛋白的收缩特性降低。相反，在 MI 大鼠中用抗氧化剂 N-乙酰半胱氨酸（NAC）治疗 4 周后，Endo 心肌细胞中超氧阴离子的产生恢复正常，肌球蛋白的收缩特性得以恢复。这种效应伴随着体内收缩力的改善。NAC 的有益作用至少部分是通过降低 PKA 活性介导的，特别是 PKA 介导的心肌肌钙蛋白 I 的过度磷酸化。
HF 期间，线粒体含量/活性的跨壁梯度丧失，并介导依赖活性氧的收缩功能障碍。
氧化还原信号的区域性改变通过 PKA 依赖性途径影响 Sub-Endo 肌球蛋白的收缩机制，导致跨壁收缩梯度丧失，并损害整体收缩性。
