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首页> 外文学位 >Regulation des hemicanaux de connexine 43: Implication dans la cardioprotection contre les lesions ischemiques.
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Regulation des hemicanaux de connexine 43: Implication dans la cardioprotection contre les lesions ischemiques.

机译：Connexin 43 hemicanalin调节：对缺血性损伤的心脏保护作用。

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摘要

Connexin 43 (Cx43) is the basic unit in the composition of Gap junction channels but also of the non-junctional unapposed hemichannels (Hc). Gap junction channels play key roles in cardiac function by allowing conduction of electrical impulses and exchange of biologically important molecules between cells. The unapposed Hc, however, perform functions different from those achieved by Gap junction channels mainly by providing pathways between the cytosol and the extracellular space allowing movement of ions and other small metabolites. Although they are much less studied than Gap junction channels, Hc are believed to remain normally in a closed state and that phosphorylation is an important factor promoting their closure. Under ischemic stress, the amount of non-phosphorylated Cx43 increases resulting in increasing hemichannels opening, an effect that can lead to irreversible tissue injury and cell death.;Protein kinase C (PKC) possesses the largest number of phosphorylation sites on Cx43 and exerts significant control on Cx43 channels. Its function depends on the involvement of at least 12 distinct isoformes. Various PKC isoforms exert specific cellular and cardiovascular functions, nonetheless the functional role of PKC isoforms in the modulation of the unapposed Cx43 hemichannels has never been assessed, neither has the therapeutic potential of Cx43Hc modulation in the protection of ischemic heart. In this context, three studies have been performed, they form the body of this thesis.;In the first study, a unique set of synthetic PKC isoform-selective activator and inhibitor peptides was utilised. In combination with the patch-clamp technique, we have demonstrated that Cx43Hc conductance is strongly inhibited by, among many isoforms, epsilon PKC isoforme, known for its cardioprotective effect against ischemic injury.;In the second study, we characterized the effect of a synthetic structural mimetic peptide of Cx43. Using patch clamp technique, we have demonstrated that the peptide Gap26 inhibits directly and specifically Cx43Hc, we also showed that Gap26 can confer resistance to cardiomyocytes (in vitro ) and intact heart (ex vivo) against ischemia.;In the third study, we investigated for the first time in vivo the capability of a unique pair of structural Cx43 mimetic peptides, Gap26 and Gap27, to protect heart from ischemic injury when administered in single low-dose intravenous boluses. We demonstrated that administration of either one or both peptides, before or after the onset of ischemia renders heart more resistant to ischemia and reduces significantly the size of myocardial infarct.;Altogether, our results revealed salvatory effect of Cx43Hc inhibition during ischemia and uncovered therapeutic potential of the synthetic structural mimetic peptides of Cx43 in ischemic heart disease.;Keywords: Heart, Ischemia, Connexin 43, Protein kinase C, Synthetic peptides.
机译：连接蛋白43（Cx43）是Gap结合通道组成的基本单位，也是非结合的非并置半通道（Hc）的基本单位。间隙连接通道通过允许电脉冲的传导和细胞之间生物学上重要分子的交换，在心脏功能中起关键作用。然而，未结合的Hc的功能与Gap结合通道所实现的功能不同，主要是通过在细胞质和细胞外空间之间提供途径，允许离子和其他小代谢物移动。尽管与Gap结合通道相比，对它们的研究较少，但据信Hc通常保持在闭合状态，磷酸化是促进其闭合的重要因素。在缺血应激下，非磷酸化Cx43的数量增加，导致半通道开放增加，这种作用可导致不可逆的组织损伤和细胞死亡。蛋白激酶C（PKC）在Cx43上具有最大的磷酸化位点，并发挥重要作用Cx43通道上的控制。它的功能取决于至少12种不同的同工型。各种PKC同工型发挥特定的细胞和心血管功能，但是，尚未评估PKC同工型在未结合的Cx43半通道调节中的功能作用，Cx43Hc调节在保护缺血性心脏病中的治疗潜力也从未得到评估。在这种情况下，已经进行了三项研究，它们构成了本文的主体。在第一项研究中，利用了一套独特的合成PKC亚型选择性激活剂和抑制剂肽。结合膜片钳技术，我们已经证明，Cx43Hc电导在许多同工型中被εPKC同工型强烈抑制，其以对缺血性损伤的心脏保护作用而闻名。在第二项研究中，我们表征了合成的作用Cx43的结构模拟肽。使用膜片钳技术，我们已经证明了Gap26肽直接抑制Cx43Hc的特异性，并且还证明了Gap26可以赋予心肌（体外）和完整的心脏（离体）抵抗缺血的抵抗力；在第三项研究中，我们进行了研究首次使用一对独特的结构性Cx43模拟肽Gap26和Gap27，在体内以单一小剂量静脉推注给药保护心脏免受缺血性损伤的能力。我们证明在缺血发作之前或之后施用一种或两种肽可使心脏对局部缺血更具抵抗力，并显着减少心肌梗塞的大小;总而言之，我们的结果表明缺血期间Cx43Hc的抑制作用具有挽救作用，并且尚未发现治疗潜力关键词：心脏，缺血，连接蛋白43，蛋白激酶C，合成肽

著录项

  • 作者

    Al Hawat, Ghayda.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 278 p.
  • 总页数 278
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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