Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
Mol Cell Biochem. 2021 Jul;476(7):2675-2684. doi: 10.1007/s11010-021-04108-2. Epub 2021 Mar 5.
Inhibition of succinate dehydrogenase (SDH) by Dimethyl Malonate (DiMal) reduces cardiac ischemia-reperfusion (IR) injury. We investigated the cardioprotective effect of DiMal in a rat model during advancing type 2 diabetes. Zucker Diabetic Fatty rats and lean controls were investigated corresponding to prediabetes, onset and mature diabetes. Hearts were mounted in an isolated perfused model, and subjected to IR for investigation of infarct size (IS) and mitochondrial respiratory control ratio (RCR). DiMal was administered for 10 min before ischemia. Compared with age-matched non-diabetic rats, prediabetic rats had larger IS (49 ± 4% vs. 36 ± 2%, p = 0.007), rats with onset diabetes smaller IS (51 ± 3% vs. 62 ± 3%, p = 0.05) and rats with mature diabetes had larger IS (79 ± 3% vs. 69 ± 2%, p = 0.06). At the prediabetic stage DiMal did not alter IS. At onset of diabetes DiMal 0.6 mM increased IS in diabetic but not in non-diabetic control rats (72 ± 4% vs. 51 ± 3%, p = 0.003). At mature diabetes DiMal 0.1 and 0.6 mM reduced IS (68 ± 3% vs. 79 ± 3% and 64 ± 5% vs. 79 ± 3%, p = 0.1 and p = 0.01), respectively. DiMal 0.1 mM alone reduced IS in age-matched non-diabetic animals (55 ± 3% vs. 69 ± 2% p = 0.01). RCR was reduced at mature diabetes but not modulated by DiMal. Modulation of SDH activity results in variable infarct size reduction depending on presence and the stage of diabetes. Modulation of SDH activity may be an unpredictable cardioprotective approach.
丙二酸二乙酯（DiMal）抑制琥珀酸脱氢酶（SDH）可减少心脏缺血再灌注（IR）损伤。我们在 2 型糖尿病进展的大鼠模型中研究了 DiMal 的心脏保护作用。Zucker 糖尿病肥胖大鼠和瘦对照大鼠分别对应于糖尿病前期、发病和成熟糖尿病。心脏在离体灌注模型中进行安装，并进行 IR 以研究梗死面积（IS）和线粒体呼吸控制比（RCR）。缺血前 10 分钟给予 DiMal。与年龄匹配的非糖尿病大鼠相比，糖尿病前期大鼠的 IS 更大（49 ± 4%比 36 ± 2%，p = 0.007），发病糖尿病大鼠的 IS 更小（51 ± 3%比 62 ± 3%，p = 0.05），成熟糖尿病大鼠的 IS 更大（79 ± 3%比 69 ± 2%，p = 0.06）。在糖尿病前期阶段，DiMal 并未改变 IS。在糖尿病发病时，0.6 mM DiMal 增加了糖尿病大鼠但未增加非糖尿病对照组大鼠的 IS（72 ± 4%比 51 ± 3%，p = 0.003）。在成熟糖尿病中，0.1 和 0.6 mM DiMal 降低了 IS（68 ± 3%比 79 ± 3%和 64 ± 5%比 79 ± 3%，p = 0.1 和 p = 0.01）。单独的 0.1 mM DiMal 降低了年龄匹配的非糖尿病动物的 IS（55 ± 3%比 69 ± 2%，p = 0.01）。RCR 在成熟糖尿病中降低，但不受 DiMal 调节。SDH 活性的调节导致梗死面积的变化，具体取决于糖尿病的存在和阶段。SDH 活性的调节可能是一种不可预测的心脏保护方法。
