Ferko M, Gvozdjaková A, Kucharská J, Mujkosová J, Waczulíková I, Styk J, Ravingerová T, Ziegelhöffer-Mihalovicová B, Ziegelhöffer A
Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia.
Gen Physiol Biophys. 2006 Dec;25(4):397-413.
Rats with streptozotocin-diabetes develop mechanisms of endogenous protection (MEP) that participate actively in functional remodeling of cardiac sarcolemma. Remodeling of sarcolemma is a sign of damage but it also protects the cells of the diabetic heart (DH) against additional energy disbalance due to excessive Ca(2+) entry. Since yet, cardiac mitochondria (MIT) were investigated predominantly from the aspect of damage only. Aims of the present study were: i) to distinguish between acute diabetes-induced changes in function of rat heart MIT which clearly belong to damage from those that reflect the MEP and participate in functional remodeling of the MIT; ii) elucidate the significance of MEP-induced changes in heart MIT for cardiac energetics. Acute diabetes (8 days) was induced in adult male Wistar rats by streptozotocin (STZ, 65 mg.kg(-1) i.p., single dose). On the day 8 after STZ administration, the diabetic animals exhibited 300-330 % increase in blood glucose, triacylglycerols and cholesterol as well as 89.6 % increase in glycohemoglobin (all p < 0.01). The blood level of insulin dropped by 53 % (p < 0.02). State 3 and state 4 oxygen consumptions of DH MIT were decreased against the controls, leading to drop of the respiratory control index (17.9 and 7.3 %) and oxidative phosphorylation rate (OPR, 27.5 and 24.6 %; all p < 0.003-0.02). These effects of damage yielding in strained energy balance of the acute DH were partially alleviated by MEP. The latter involved temporary preservation of the ADP : O ratio, with participation of elevated MIT Mg(2+)-ATPase activity as well as increased formation of MIT substrate and energy transition pores (both p < 0.05). Hence, the energy disbalance of the acute DH was finally manifested in 13 % loss in its AMP content only (p < 0.05). Results indicate that MIT in STZ-DH are functionally remodeled. Defective O2 consumption by MIT renders molecular changes suggestive of a mild hypoxic state but an increase in Mg(2+)-ATPase activity and facilitated energy delivery from MIT to the cytoplasm indicate the presence of MEP acting in the MIT and alleviating the effect of decreased oxidative energy production in the acute DH.
链脲佐菌素诱导糖尿病的大鼠会形成内源性保护机制（MEP），该机制积极参与心肌肌膜的功能重塑。肌膜重塑是损伤的标志，但它也能保护糖尿病心脏（DH）细胞免受因过量钙离子内流导致的额外能量失衡影响。迄今为止，心脏线粒体（MIT）主要仅从损伤方面进行研究。本研究的目的是：i）区分急性糖尿病诱导的大鼠心脏MIT功能变化中，哪些明显属于损伤，哪些反映了MEP并参与MIT的功能重塑；ii）阐明MEP诱导的心脏MIT变化对心脏能量代谢的意义。通过链脲佐菌素（STZ，65mg·kg⁻¹腹腔注射，单剂量）诱导成年雄性Wistar大鼠发生急性糖尿病（8天）。在注射STZ后的第8天，糖尿病动物的血糖、三酰甘油和胆固醇水平升高300 - 330%，糖化血红蛋白升高89.6%（均p < 0.01）。胰岛素血水平下降53%（p < 0.02）。与对照组相比，DH MIT的状态3和状态4氧消耗量降低，导致呼吸控制指数下降（17.9%和7.3%）以及氧化磷酸化率（OPR，27.5%和24.6%；均p < 0.003 - 0.02）。MEP部分缓解了这些导致急性DH能量平衡紧张的损伤效应。MEP包括暂时维持ADP : O比值，这与MIT的镁离子 - ATP酶活性升高以及MIT底物和能量转换孔的形成增加有关（均p < 0.05）。因此，急性DH的能量失衡最终仅表现为其AMP含量降低13%（p < 0.05）。结果表明，STZ - DH中的MIT在功能上发生了重塑。MIT的氧气消耗缺陷导致分子变化提示轻度缺氧状态，但镁离子 - ATP酶活性增加以及MIT向细胞质的能量传递促进表明存在作用于MIT的MEP，减轻了急性DH中氧化能量产生减少的影响。
