Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor.
Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor.
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DOI：
10.1016/j.brainres.2016.11.012
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发表时间：
2017-01-15
期刊：
影响因子：
2.9
通讯作者：
Paisansathan C
中科院分区：
文献类型：
--
作者：
Vetri F;Qi M;Xu H;Oberholzer J;Paisansathan C
链脲佐菌素（STZ）诱导的慢性高血糖症对神经血管偶联有不利影响，与PKC介导的磷酸化和PKC亚型表达变化增加有关。在此，我们试图确定：1）选择性PKC-α/β/γ抑制剂GF 109203 X是否可以逆转慢性高血糖对脑血管反应性的影响; 2）胰岛移植是否可以预防1型糖尿病大鼠模型中观察到的脑血管损伤的发展。我们研究了GF 109203 X在糖尿病（DM）、非糖尿病（ND）和移植（TR）刘易斯大鼠中在坐骨神经刺激（SNS）或局部应用大电导Ca 2+操作的K+（BKCa）通道开放剂NS 1619或K+内向整流（Kir）通道激动剂KCl期间的作用。采用闭合颅窗活体显微镜技术监测软脑膜小动脉直径变化。与ND或TR大鼠相比，DM大鼠与SNS相关的软脑膜小动脉扩张反应降低约45%。此外，软脑膜小动脉扩张局部氯化钾和NS 1619在很大程度上减弱DM大鼠，但不是在ND或TR动物。这些反应通过将GF 109203 X急性应用于脑表面而完全恢复。PKC抑制剂对血糖正常和TR动物的血管反应没有影响。总之，糖尿病相关的神经血管偶联慢性损伤可通过PKC-α/β/γ抑制剂逆转或通过胰岛移植预防。我们认为，特定的PCK亚型（α/β/γ）与高血糖症中观察到的神经血管解偶联机制相关。
Streptozotocin (STZ)-induced chronic hyperglycemia has a detrimental effect on neurovascular coupling, linked to increased PKC-mediated phosphorylation and PKC isoform expression changes. Here, we sought to determine whether: 1) selective PKC-α/β/γ inhibitor, GF109203X, could reverse the effects of chronic hyperglycemia on cerebrovascular reactivity; 2) pancreatic islet transplantation could prevent the development of cerebrovascular impairment seen in a rat model of Type 1 Diabetes. We studied the effect of GF109203X in diabetic (DM), non-diabetic (ND), and transplanted (TR) Lewis rats during either sciatic nerve stimulation (SNS) or the topical applications of the large-conductance Ca2+-operated K+ (BKCa) channel opener, NS1619, or the K+ inward rectifier (Kir) channel agonist, KCl. Pial arteriole diameter changes were monitored using a closed cranial window in vivo microscopy technique. The pial arteriole dilatory response associated with SNS was decreased by ~45%, when comparing DM vs either ND or TR rats. Also, pial arteriolar dilations to topical KCl and NS1619 were largely attenuated in DM rats, but not in ND or TR animals. These responses were completely restored by the acute application of GF109203X to the brain surface. The PKC inhibitor had no effect on vascular responses in normoglycemic and TR animals. In conclusion, DM-associated chronic impairment of neurovascular coupling may be readily reversed by a PKC-α/β/γ inhibitor or prevented via pancreatic islet transplantation. We believe that specific PCK isoforms (α/β/γ) are mechanistically linked to the neurovascular uncoupling seen with hyperglycemia.
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