Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom.
Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, German Center for Cardiovascular Research (DZHK) partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
Elife. 2020 Mar 31;9:e52221. doi: 10.7554/eLife.52221.
Cardiomyocyte β-adrenoceptors (β-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
已证实，与可溶性鸟苷酸环化酶（sGC）偶联、可产生第二信使 3'，5'-环鸟苷单磷酸（cGMP）的心肌细胞 β-肾上腺素能受体（β-AR）可预防心力衰竭。然而，在健康和疾病中，这些受体在精细膜结构中的确切定位以及 β-AR/cGMP 信号的亚细胞区室化，对于理解这种保护作用仍然难以捉摸。在这里，我们使用基于Förster 共振能量转移（FRET）的 cGMP 生物传感器结合扫描离子电导显微镜（SICM），显示健康大鼠心肌细胞中的功能性 β-AR 主要局限于 T 小管。心肌梗死引起的心力衰竭导致这些受体产生的 cGMP 水平降低，并改变了 cGMP 的亚细胞区室化。此外，减弱的 cGMP 信号导致依赖磷酸二酯酶 2 的负 cGMP-cAMP 交叉对话受损。总之，心力衰竭时β-AR/cGMP 信号转导体发生了拓扑和功能重组，在设计通过该受体发挥作用的新疗法时应考虑到这一点。
