Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
J Cardiovasc Pharmacol. 2010 Mar;55(3):248-54. doi: 10.1097/FJC.0b013e3181cf0090.
Intracellular [Ca2+]i overloading in cardiomyocytes is a fundamental pathogenic event associated with chronic aldosterone/salt treatment (ALDOST) and accounts for an induction of oxidative stress that leads to necrotic cell death and consequent myocardial scarring. This prooxidant response to Ca2+ overloading in cardiac myocytes and mitochondria is intrinsically coupled to simultaneous increased Zn2+ entry serving as an antioxidant. Herein, we investigated whether Ca2+ and Zn2+ dyshomeostasis and prooxidant to antioxidant dysequilibrium seen at 4 weeks, the pathologic stage of ALDOST, could be uncoupled in favor of antioxidants, using cotreatment with a ZnSO4 supplement; pyrrolidine dithiocarbamate (PDTC), a Zn2+ ionophore; or ZnSO4 in combination with amlodipine (Amlod), a Ca2+ channel blocker. We monitored and compared responses in cardiomyocyte free [Ca2+]i and [Zn2+]i together with biomarkers of oxidative stress in cardiac myocytes and mitochondria. At week 4 of ALDOST and compared with controls, we found (1) an elevation in [Ca2+]i coupled with [Zn2+]i and (2) increased mitochondrial H2O2 production and increased mitochondrial and cardiac 8-isoprostane levels. Cotreatment with the ZnSO4 supplement alone, PDTC, or ZnSO4+Amlod augmented the rise in cardiomyocyte [Zn2+]i beyond that seen with ALDOST alone, whereas attenuating the rise in [Ca2+]i, which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca2+ and Zn2+ was demonstrated in cardiac myocytes and mitochondria during 4-week ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca2+ and Zn2+ dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn2+]i and/or reducing [Ca2+]i using cotreatment with ZnSO4 or PDTC alone or ZnSO4+Amlod in combination.
心肌细胞内 [Ca2+]i 超载是与慢性醛固酮/盐处理 (ALDOST) 相关的基本致病事件，可导致氧化应激诱导，进而导致坏死性细胞死亡和随后的心肌瘢痕形成。这种钙超载在心肌细胞和线粒体中产生的促氧化剂反应与同时增加的 Zn2+ 内流内在耦合，起到抗氧化剂的作用。在此，我们研究了在 4 周的病理阶段 ALDOST 中观察到的 Ca2+ 和 Zn2+ 动态平衡紊乱和促氧化剂与抗氧化剂失衡是否可以通过同时使用 ZnSO4 补充剂、Zn2+ 载体吡啶二硫代氨基甲酸酯 (PDTC) 或 ZnSO4 与氨氯地平 (Amlod) 联合治疗来实现解偶联，这是一种 Ca2+ 通道阻滞剂。我们监测并比较了心肌细胞游离 [Ca2+]i 和 [Zn2+]i 以及心肌细胞和线粒体中氧化应激生物标志物的反应。在 ALDOST 的第 4 周与对照组相比，我们发现 (1) [Ca2+]i 升高与 [Zn2+]i 升高有关，(2) 线粒体 H2O2 产生增加，线粒体和心脏 8-异前列腺素水平升高。单独使用 ZnSO4 补充剂、PDTC 或 ZnSO4+Amlod 治疗可使心肌细胞 [Zn2+]i 的升高超过单独 ALDOST 时的升高，同时减轻 [Ca2+]i 的升高，从而降低氧化应激。因此，在 4 周的 ALDOST 期间，在心肌细胞和线粒体中证明了细胞内 Ca2+ 和 Zn2+ 的耦合失调，其中促氧化剂压倒了抗氧化防御。这种内在耦合的 Ca2+ 和 Zn2+ 动态平衡失调可以通过单独使用 ZnSO4 或 PDTC 或 ZnSO4+Amlod 联合治疗来增加游离 [Zn2+]i 和/或降低 [Ca2+]i 来实现解偶联，从而有利于抗氧化防御。
