Inhibition of calcium/calmodulin-dependent kinase II restores contraction and relaxation in isolated cardiac muscle from type 2 diabetic rats.
Inhibition of calcium/calmodulin-dependent kinase II restores contraction and relaxation in isolated cardiac muscle from type 2 diabetic rats.
复制标题
抑制钙/钙调素依赖性激酶II可恢复2型糖尿病大鼠离体心肌的收缩和舒张。
DOI：
10.1186/s12933-018-0732-x
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发表时间：
2018-06-14
影响因子：
9.3
通讯作者：
Erickson JR
中科院分区：
文献类型：
--
作者：
Daniels LJ;Wallace RS;Nicholson OM;Wilson GA;McDonald FJ;Jones PP;Baldi JC;Lamberts RR;Erickson JR
钙/钙调蛋白依赖性激酶 II-δ (CaMKIIδ) 活性在高血糖期间增强，并已被证明会改变心肌细胞内的钙处理，最终导致心脏功能下降。然而，CaMKIIδ 对 2 型糖尿病期间心肌收缩力的影响尚不清楚。我们使用免疫印迹法检测了射血分数保留的非糖尿病和 2 型糖尿病患者（每组 n = 7 名患者）的右心耳中以及 Zucker 糖尿病脂肪大鼠 (ZDF)（每组 n = 5-10 只动物）的右心室组织中 CaMKIIδ 在早期糖尿病心功能障碍期间的表达和激活。我们还使用超声心动图测量了 ZDF 和对照大鼠的整个心脏功能。然后我们测量了来自 ZDF 的分离小梁的收缩和松弛参数，以在存在和不存在 CaMKII 抑制剂的情况下控制大鼠。在糖尿病人和动物组织中，CaMKIIδ 磷酸化（Thr287）均增加，表明 2 型糖尿病心脏中 CaMKIIδ 激活增加。糖尿病大鼠心肌的基础心肌收缩力和舒张力受损，而用 KN93 抑制 CaMKII 部分恢复了收缩力和舒张力。 Autocamtide-2 相关抑制肽 (AIP) 是另一种 CaMKII 抑制剂，其作用机制与 KN93 不同，可完全恢复心肌收缩力和舒张性。我们的结果表明，CaMKIIδ 在调节糖尿病心脏功能方面发挥着关键作用，此外，表明 CaMKII 抑制剂在改善 2 型糖尿病期间的心肌功能方面具有潜在的治疗作用。
Calcium/calmodulin-dependent kinase II-delta (CaMKIIδ) activity is enhanced during hyperglycemia and has been shown to alter intracellular calcium handling in cardiomyocytes, ultimately leading to reduced cardiac performance. However, the effects of CaMKIIδ on cardiac contractility during type 2 diabetes are undefined. We examined the expression and activation of CaMKIIδ in right atrial appendages from non-diabetic and type 2 diabetic patients (n = 7 patients per group) with preserved ejection fraction, and also in right ventricular tissue from Zucker Diabetic Fatty rats (ZDF) (n = 5–10 animals per group) during early diabetic cardiac dysfunction, using immunoblot. We also measured whole heart function of ZDF and control rats using echocardiography. Then we measured contraction and relaxation parameters of isolated trabeculae from ZDF to control rats in the presence and absence of CaMKII inhibitors. CaMKIIδ phosphorylation (at Thr287) was increased in both the diabetic human and animal tissue, indicating increased CaMKIIδ activation in the type 2 diabetic heart. Basal cardiac contractility and relaxation were impaired in the cardiac muscles from the diabetic rats, and CaMKII inhibition with KN93 partially restored contractility and relaxation. Autocamtide-2-related-inhibitor peptide (AIP), another CaMKII inhibitor that acts via a different mechanism than KN93, fully restored cardiac contractility and relaxation. Our results indicate that CaMKIIδ plays a key role in modulating performance of the diabetic heart, and moreover, suggest a potential therapeutic role for CaMKII inhibitors in improving myocardial function during type 2 diabetes.
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影响因子：
5.1
作者：
Guariguata, L.;Whiting, D. R.;Shaw, J. E.
通讯作者：
Shaw, J. E.
影响因子：
5
作者：
Hidalgo, Carlos G.;Chung, Charles S.;Saripalli, Chandra;Methawasin, Mei;Hutchinson, Kirk R.;Tsaprailis, George;Labeit, Siegfried;Mattiazzi, Alicia;Granzier, Henk L.
通讯作者：
Granzier, Henk L.
影响因子：
16.2
作者：
Chudyk A;Petrella RJ
通讯作者：
Petrella RJ
影响因子：
8.2
作者：
Bugger, Heiko;Abel, E. Dale
通讯作者：
Abel, E. Dale
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