Kokoz Yuri M, Evdokimovskii Edward V, Maltsev Alexander V, Nenov Miroslav N, Nakipova Olga V, Averin Alexey S, Pimenov Oleg Yu, Teplov Ilia Y, Berezhnov Alexey V, Reyes Santiago, Alekseev Alexey E
Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
J Mol Cell Cardiol. 2016 Nov;100:9-20. doi: 10.1016/j.yjmcc.2016.09.006. Epub 2016 Sep 19.
Sustained cardiac adrenergic stimulation has been implicated in the development of heart failure and ventricular dysrhythmia. Conventionally, α2 adrenoceptors (α2-AR) have been assigned to a sympathetic short-loop feedback aimed at attenuating catecholamine release. We have recently revealed the expression of α2-AR in the sarcolemma of cardiomyocytes and identified the ability of α2-AR signaling to suppress spontaneous Ca transients through nitric oxide (NO) dependent pathways. Herein, patch-clamp measurements and serine/threonine phosphatase assay revealed that, in isolated rat cardiomyocytes, activation of α2-AR suppressed L-type Ca current (I) via stimulation of NO synthesis and protein kinase G- (PKG) dependent activation of phosphatase reactions, counteracting isoproterenol-induced β-adrenergic activation. Under stimulation with norepinephrine (NE), an agonist of β- and α-adrenoceptors, the α2-AR antagonist yohimbine substantially elevated I at NE levels >10nM. Concomitantly, yohimbine potentiated triggered intracellular Ca dynamics and contractility of cardiac papillary muscles. Therefore, in addition to the α2-AR-mediated feedback suppression of sympathetic and adrenal catecholamine release, α2-AR in cardiomyocytes can govern a previously unrecognized local cardiomyocyte-delimited stress-reactive signaling pathway. We suggest that such aberrant α2-AR signaling may contribute to the development of cardiomyopathy under sustained sympathetic drive. Indeed, in cardiomyocytes of spontaneously hypertensive rats (SHR), an established model of cardiac hypertrophy, α2-AR signaling was dramatically reduced despite increased α2-AR mRNA levels compared to normal cardiomyocytes. Thus, targeting α2-AR signaling mechanisms in cardiomyocytes may find implications in medical strategies against maladaptive cardiac remodeling associated with chronic sympathoadrenal stimulation.
持续性心脏肾上腺素能刺激与心力衰竭和室性心律失常的发生有关。传统上，α2肾上腺素能受体（α2-AR）被认为参与交感神经短环反馈，旨在减弱儿茶酚胺释放。我们最近发现α2-AR在心肌细胞肌膜上表达，并确定α2-AR信号传导通过一氧化氮（NO）依赖途径抑制自发性钙瞬变的能力。在此，膜片钳测量和丝氨酸/苏氨酸磷酸酶测定显示，在分离的大鼠心肌细胞中，α2-AR的激活通过刺激NO合成和蛋白激酶G（PKG）依赖性磷酸酶反应激活来抑制L型钙电流（I），抵消异丙肾上腺素诱导的β-肾上腺素能激活。在用去甲肾上腺素（NE）刺激时，β-和α-肾上腺素能受体的激动剂，α2-AR拮抗剂育亨宾在NE水平>10nM时显著升高I。同时，育亨宾增强了触发的细胞内钙动力学和心脏乳头肌的收缩力。因此，除了α2-AR介导的对交感神经和肾上腺儿茶酚胺释放的反馈抑制外，心肌细胞中的α2-AR还可以控制一种以前未被认识的局部心肌细胞限定的应激反应信号通路。我们认为，这种异常的α2-AR信号传导可能在持续交感神经驱动下导致心肌病的发生。事实上，在自发性高血压大鼠（SHR）的心肌细胞中，一种已建立的心脏肥大模型，尽管与正常心肌细胞相比α2-AR mRNA水平升高，但α2-AR信号传导却显著降低。因此，针对心肌细胞中α2-AR信号传导机制可能在对抗与慢性交感肾上腺刺激相关的适应性不良心脏重塑的医学策略中具有意义。
