Centre Hospitalier de L'Université de Montréal Research Center, and Departments of Medicine and Pharmacology, Université de Montréal, Montreal, Québec, Canada.
Can J Cardiol. 2012 Sep-Oct;28(5):590-8. doi: 10.1016/j.cjca.2012.02.007. Epub 2012 Apr 6.
The centrally-acting sympatholytic imidazoline compound, moxonidine, prevents the development of left ventricular hypertrophy and attenuates maladaptive proliferative signalling as well as downstream apoptotic pathways in spontaneously hypertensive rat and cardiomyopathic hamster hearts. The actions are selectively mediated by imidazoline type-1 receptor (I(1)-receptor, also named nischarin), nonadrenergic neurotransmitter receptors mainly found in the brainstem medulla. We identified cardiac I(1)-receptors/nischarin and showed that they are upregulated in cardiovascular disorders, and are functional without the central nervous system's contribution. Molecular characterization revealed that I(1)-receptor/nischarin has a unique structure with multifunctional domains allowing it to perform a number of cell signalling roles as a scaffolding protein. Nischarin has been associated with integrin α5 and inhibition of Rac1 and was shown to interact with insulin receptor substrates. However, very little is known about cardiac I(1)-receptor/nischarin and its role(s) in normal physiology and pathophysiology, specifically in cardiac remodelling. Our studies have shown that I(1)-receptor is expressed in cardiac fibroblasts and myocytes and that in vitro I(1)-receptor activation inhibits norepinephrine-induced cardiomyocyte apoptosis and fibroblast proliferation, through differential effects on mitogen-activated protein kinases and Akt. Accordingly, apart from centrally-mediated sympatholytic function, I(1)-receptor in the heart may control cell growth and death. I(1)-receptor may be implicated in cardiac remodelling and dysfunction, through the inhibition of apoptotic pathways and/or activation of survival pathways, in a cell-specific manner. Identification of the cardioprotective mechanisms of cardiac I(1)-receptor could result in specifically-tailored cell/gene-driven I(1)-receptor treatments, and/or treatments that target cardiac I(1)-receptor, which could eventually be important for patients with hypertrophic heart disease.
中枢作用的拟交感神经咪唑啉化合物莫索尼定可预防左心室肥厚的发展，并减弱自发性高血压大鼠和心肌病仓鼠心脏中适应性增殖信号以及下游凋亡途径。这些作用是通过咪唑啉 I 型受体（I1-受体，也称为尼沙林）选择性介导的，该受体是非肾上腺素能神经递质受体，主要存在于脑干延髓。我们鉴定了心脏 I1-受体/尼沙林，并表明它们在心血管疾病中上调，并且在没有中枢神经系统贡献的情况下具有功能。分子特征表明，I1-受体/尼沙林具有独特的结构，具有多功能结构域，使其能够作为支架蛋白执行多种细胞信号作用。尼沙林与整合素 α5 有关，可抑制 Rac1，并显示与胰岛素受体底物相互作用。然而，关于心脏 I1-受体/尼沙林及其在正常生理和病理生理学中的作用（特别是在心脏重塑中）知之甚少。我们的研究表明，I1-受体在心肌细胞和成纤维细胞中表达，并且在体外，I1-受体激活通过对丝裂原激活的蛋白激酶和 Akt 的不同作用抑制去甲肾上腺素诱导的心肌细胞凋亡和成纤维细胞增殖。因此，除了中枢介导的交感神经抑制作用外，心脏中的 I1-受体还可能通过抑制凋亡途径和/或激活存活途径，以细胞特异性方式控制细胞生长和死亡。鉴定心脏 I1-受体的心脏保护机制可能导致针对心脏 I1-受体的特异性细胞/基因驱动的 I1-受体治疗，以及针对心脏 I1-受体的治疗，这对于肥厚性心脏病患者最终可能很重要。
