Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts
Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts
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DOI：
10.1161/jaha.119.012273
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发表时间：
2019-08-06
影响因子：
5.4
通讯作者：
Xiang, Yang K.
中科院分区：
文献类型：
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作者：
West, Toni M.;Wang, Qingtong;Xiang, Yang K.
背景：在小鼠心力衰竭模型和糖尿病相关性心脏肥厚患者中，西地那非抑制磷酸二酯酶5 （PDE5）可改善心脏预后。然而，西地那非改善心功能的机制尚不清楚。我们已经观察到PDE5和β 2肾上腺素能受体（β 2AR）之间的关系，这是一种新的机制轴，西地那非可以改善糖尿病性心肌病的症状。方法与结果：采用西地那非治疗高脂饲料（HFD）野生型和β 2AR基因敲除小鼠，并进行超声心动图分析。分离心肌细胞进行兴奋-收缩（E-C）偶联、荧光共振能量转移和近端结扎试验；同时对心脏组织进行生化和组织学分析。PDE5选择性地与β 2AR结合，但不与β 1肾上腺素能受体结合，西地那非抑制PDE5可恢复HFD小鼠和分离心室肌细胞对肾上腺素能刺激的受损反应。西地那非增强HFD肌细胞β肾上腺素能受体（β AR）刺激的cGMP和cAMP信号。因此，抑制PDE5导致蛋白激酶G-，并在较小程度上导致钙/钙调素依赖性激酶ii依赖性肾上腺素刺激的E-C偶联的改善。删除β 2AR可消除西地那非的作用。尽管pde5 - β 2AR的关联在HFD中没有改变，但磷酸二酯酶3在HFD肌细胞中与β 2AR- pde5复合物的关联增加。结论：本研究阐明了β 2AR-PDE5轴可靶向治疗糖尿病性心肌病的机制。抑制PDE5可增强HFD肌细胞中β 2AR对cGMP和cAMP信号的刺激，以及蛋白激酶g依赖性E-C偶联。
Background-In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and beta 2 adrenergic receptor (beta 2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy.Methods and Results-Wild-type and beta 2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with beta 2AR, but not beta 1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances beta adrenergic receptor (beta AR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of beta 2AR abolishes sildenafil's effect. Although the PDE5-beta 2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the beta 2AR-PDE5 complex in HFD myocytes.Conclusions-This study elucidates mechanisms by which the beta 2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances beta 2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.