Precision medicine approach: Empagliflozin for diabetic cardiomyopathy in mice with aldehyde dehydrogenase (ALDH) 2 * 2 mutation, a specific genetic mutation in millions of East Asians.
Precision medicine approach: Empagliflozin for diabetic cardiomyopathy in mice with aldehyde dehydrogenase (ALDH) 2 * 2 mutation, a specific genetic mutation in millions of East Asians.
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DOI：
10.1016/j.ejphar.2018.09.021
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发表时间：
2018-11-15
影响因子：
5
通讯作者：
Palaniyandi SS
中科院分区：
文献类型：
--
作者：
Pan G;Deshpande M;Pang H;Palaniyandi SS
绝大多数2型糖尿病患者（约65%）死于心血管并发症，包括心力衰竭（HF）。在糖尿病心脏中，4-羟基-2-壬烯醛（4 HNE）（一种在脂质过氧化时产生的反应性醛）的水平增加。我们还证明，在糖尿病心脏中，存在醛脱氢酶（ALDH）2的活性降低，ALDH 2是心脏线粒体中存在的主要解毒酶。在东亚人中，ALDH 2的E487 K处的单点突变被称为ALDH 2 * 2，其本质上降低了ALDH 2的活性。我们假设恩格列净（EMP），一种钠-葡萄糖协同转运蛋白（SGLT）2抑制剂，可以通过减少ALDH 2 * 2突变小鼠中高血糖介导的4 HNE蛋白加合物来改善糖尿病性心肌病，因为它们模拟ALDH 2 * 2携带者，作为精确的药物工具。我们通过高脂肪饮食在11-14个月大的雄性和雌性ALDH 2 * 2小鼠中诱导2型糖尿病。喂食饲料的ALDH 2 * 2小鼠作为对照。在4个月结束时，我们用EMP（3 mg/kg/d）或其溶剂（Veh）治疗糖尿病ALDH 2 * 2小鼠。EMP治疗2个月后，通过平板运动负荷后的意识超声心动图评估心功能。与Veh处理的ALDH 2 * 2糖尿病小鼠相比，EMP显著改善了心脏功能和跑步距离和持续时间。这些有益作用可归因于EMP介导的心脏线粒体4 HNE加合物的减少以及ALDH 2 *2突变型糖尿病小鼠骨骼肌组织中磷酸化AKT、AKT、磷酸化Akt底物160 kDa（pAS 160）、AS 160和GLUT-4水平的增加。最后，我们的数据暗示EMP可以改善糖尿病ALDH 2 * 2突变患者的糖尿病心肌病。
A vast majority of type-2 diabetic patients (~65%) die of cardiovascular complications including heart failure (HF). In diabetic hearts, levels of 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde that is produced upon lipid peroxidation, were increased. We also demonstrated that in diabetic hearts, there is a decrease in the activity of aldehyde dehydrogenase (ALDH) 2, a primary detoxifying enzyme present in cardiac mitochondria. A single point mutation at E487K of ALDH2 in East Asians known as ALDH2 * 2 intrinsically lowers ALDH2 activity. We hypothesize that Empagliflozin (EMP), a sodium-glucose cotransporter (SGLT) 2 inhibitor, can ameliorate diabetic cardiomyopathy by decreasing hyperglycemia-mediated 4HNE protein adducts in ALDH2 * 2 mutant mice which serve as a precision medicine tool as they mimic ALDH2 * 2 carriers. We induced type-2 diabetes in 11–14 month-old male and female ALDH2 * 2 mice through a high-fat diet. Chow-fed ALDH2 * 2 mice served as controls. At the end of 4 months, we treated the diabetic ALDH2 * 2 mice with EMP (3 mg/kg/d) or its vehicle (Veh). After 2 months of EMP treatment, cardiac function was assessed by conscious echocardiography after treadmill exercise stress. EMP improved the cardiac function and running distance and duration significantly compared to Veh-treated ALDH2 * 2 diabetic mice. These beneficial effects can be attributed to the EMP-mediated decrease in cardiac mitochondrial 4HNE adducts and increase in the levels of phospho AKT, AKT, phospho Akt substrate of 160 kDa (pAS160), AS160 and GLUT-4 in the skeletal muscle tissue of the ALDH2*2 mutant diabetic mice, respectively. Finally, our data implicate EMP can ameliorate diabetic cardiomyopathy in diabetic ALDH2 * 2 mutant patients.
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影响因子：
9.3
作者：
Budas, Grant R.;Disatnik, Marie-Helene;Mochly-Rosen, Dana
通讯作者：
Mochly-Rosen, Dana
DOI：
10.1177/1535370213520109
发表时间：
2014-05
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
--
作者：
Mali VR;Ning R;Chen J;Yang XP;Xu J;Palaniyandi SS
通讯作者：
Palaniyandi SS
影响因子：
7.7
作者：
Karlsson, HKR;Zierath, JR;Wallberg-Henriksson, H
通讯作者：
Wallberg-Henriksson, H
影响因子：
5.1
作者：
Ogurtsova, K.;Fernandes, J. D. da Rocha;Makaroff, L. E.
通讯作者：
Makaroff, L. E.
影响因子：
2.9
作者：
Humphries, KM;Yoo, Y;Szweda, LI
通讯作者：
Szweda, LI