Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling.
Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling.
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DOI：
10.3389/fphys.2012.00292
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发表时间：
2012
影响因子：
4
通讯作者：
Lacombe VA
中科院分区：
文献类型：
--
作者：
Kranstuber AL;Del Rio C;Biesiadecki BJ;Hamlin RL;Ottobre J;Gyorke S;Lacombe VA
糖尿病性心脏病是一种独特的临床实体，可进展为心力衰竭和猝死。然而，糖尿病期间兴奋-收缩偶联改变导致心功能障碍的机制尚不清楚。高血糖是糖尿病的标志性疾病，导致包括肌浆网（SR）Ca 2+调节蛋白在内的长寿命蛋白上形成晚期糖基化终产物（AGEs）。然而，它们对心肌细胞SR Ca 2+处理的致病作用尚不清楚。因此，我们研究了AGE交联破坏剂是否可以防止SR Ca 2+循环的改变，从而导致糖尿病期间体内心功能障碍。链脲佐菌素诱导的糖尿病大鼠用氯化阿格列汀（ALT-711）治疗8周，并与年龄匹配的安慰剂治疗的糖尿病大鼠和健康大鼠进行比较。通过超声心动图检查评估心脏功能。分离心室肌细胞，通过共聚焦成像和定量Western印迹评估SR Ca 2+循环。糖尿病导致体内心功能不全，ALT-711治疗通过降低等容舒张时间和心肌性能指数（MPI）（与未治疗的糖尿病大鼠相比，分别降低27%和41%，P < 0.05）而部分减轻舒张功能不全。在心肌细胞中，糖尿病诱导的胞浆Ca 2+瞬时清除延长43%，SR Ca 2+负荷降低25%（P < 0.05）; ALT-711治疗后，这些参数部分改善。在未治疗的糖尿病大鼠的心肌中，SERCA 2a和RyR 2蛋白表达显著降低（与对照相比分别降低64%和36%，P < 0.05），但与对照相比，在治疗的糖尿病组中保持不变。总的来说，我们的研究结果表明，在1型糖尿病模型中，AGE积累主要损害心肌细胞中SR Ca 2+的再摄取，并且长期使用AGE交联破坏剂治疗可使SR Ca 2+处理部分正常化并改善糖尿病心肌病。
Diabetic heart disease is a distinct clinical entity that can progress to heart failure and sudden death. However, the mechanisms responsible for the alterations in excitation-contraction coupling leading to cardiac dysfunction during diabetes are not well known. Hyperglycemia, the landmark of diabetes, leads to the formation of advanced glycation end products (AGEs) on long-lived proteins, including sarcoplasmic reticulum (SR) Ca2+ regulatory proteins. However, their pathogenic role on SR Ca2+ handling in cardiac myocytes is unknown. Therefore, we investigated whether an AGE cross-link breaker could prevent the alterations in SR Ca2+ cycling that lead to in vivo cardiac dysfunction during diabetes. Streptozotocin-induced diabetic rats were treated with alagebrium chloride (ALT-711) for 8 weeks and compared to age-matched placebo-treated diabetic rats and healthy rats. Cardiac function was assessed by echocardiographic examination. Ventricular myocytes were isolated to assess SR Ca2+ cycling by confocal imaging and quantitative Western blots. Diabetes resulted in in vivo cardiac dysfunction and ALT-711 therapy partially alleviated diastolic dysfunction by decreasing isovolumetric relaxation time and myocardial performance index (MPI) (by 27 and 41% vs. untreated diabetic rats, respectively, P < 0.05). In cardiac myocytes, diabetes-induced prolongation of cytosolic Ca2+ transient clearance by 43% and decreased SR Ca2+ load by 25% (P < 0.05); these parameters were partially improved after ALT-711 therapy. SERCA2a and RyR2 protein expression was significantly decreased in the myocardium of untreated diabetic rats (by 64 and 36% vs. controls, respectively, P < 0.05), but preserved in the treated diabetic group compared to controls. Collectively, our results suggest that, in a model of type 1 diabetes, AGE accumulation primarily impairs SR Ca2+ reuptake in cardiac myocytes and that long-term treatment with an AGE cross-link breaker partially normalized SR Ca2+ handling and improved diabetic cardiomyopathy.
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影响因子：
8.2
作者：
Cooper, ME;Thallas, V;Soulis, T
通讯作者：
Soulis, T
DOI：
10.1152/ajpheart.00313.2002
发表时间：
2002-10-01
影响因子：
4.8
作者：
Choi, KM;Zhong, Y;Matlib, MA
通讯作者：
Matlib, MA
影响因子：
7.7
作者：
Bidasee, KR;Nallani, K;Besch, HR
通讯作者：
Besch, HR
DOI：
10.1073/pnas.040558497
发表时间：
2000-03-14
影响因子：
11.1
作者：
Asif, M;Egan, J;Regan, TJ
通讯作者：
Regan, TJ
影响因子：
5.3
作者：
Meurs, Kathryn M.;Lacombe, Veronique A.;Kittleson, Mark D.
通讯作者：
Kittleson, Mark D.