Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.
Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation.
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DOI：
10.1161/circheartfailure.117.004740
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
Kass DA
中科院分区：
文献类型：
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作者：
Nakamura T;Zhu G;Ranek MJ;Kokkonen-Simon K;Zhang M;Kim GE;Tsujita K;Kass DA
刺激可溶性鸟苷酸环化酶（sGC）或抑制5型磷酸二酯酶（PDE 5）可激活蛋白激酶G-1α（PKG 1 α），以对抗心肌肥大和心力衰竭。PKG 1 α作用于局部细胞内结构域;然而，其在连接同源单体的半胱氨酸-42处的氧化改变了这种定位，损害了对病理性心脏应激的抑制。由于PDE 5和sGC位于不同的微区，我们推测PKG 1 α氧化也可能对药理学调节的作用产生不同影响。对表达氧化还原死亡PKG 1 α（PKG 1 α C42 S）或同窝对照（PKG 1 αWT）的敲入小鼠进行经主动脉缩窄（TAC）以诱导压力超负荷，并使用PDE 5抑制剂（西地那非，SIL）、sGC激活剂（BAY-602770，BAY）或溶剂处理。在PKG 1 αWT对照中，SIL和BAY类似地增强了PKG活性，并减少了TAC后的病理性肥大/纤维化和心功能障碍。然而，SIL在PKG 1 α C42 S中未能保护心脏，而BAY则激活PKG，从而促进保护作用。这与PKG 1 α C42 S TAC中的最小PDE 5活化（与对照组中的较高活性相比）以及PDE 5与PKG 1 α C42 S在应激肌细胞中几乎不共定位（与PKG 1 αWT共定位相比）相对应。在应激心脏和肌细胞中，PKG 1 α C42二硫键形成有助于PDE 5活化。这增强了PDE 5的病理作用，因此反过来增强了其抑制的治疗效果。PKG 1 α氧化不会改变sGC激活的益处。这一发现有利于使用sGC激活剂，而不考虑PKG 1 α氧化，并可能有助于指导利用cGMP/PKG途径治疗心脏病的精确治疗。
Stimulation of soluble guanylate cyclase (sGC) or inhibition of phosphodiesterase type-5 (PDE5) activates protein kinase G-1α (PKG1α) to counteract cardiac hypertrophy and failure. PKG1α acts within localized intracellular domains; however, its oxidation at cysteine-42, linking homo-monomers, alters this localization, impairing suppression of pathological cardiac stress. Since PDE5 and sGC reside in separate micro-domains, we speculated that PKG1α oxidation might also differentially influence the effects from their pharmacological modulation. Knock-in mice expressing a redox-dead PKG1α (PKG1αC42S) or littermate controls (PKG1αWT) were subjected to trans-aortic constriction (TAC) to induce pressure-overload, and treated with a PDE5 inhibitor (sildenafil, SIL), sGC activator (BAY-602770, BAY), or vehicle. In PKG1αWT controls, SIL and BAY similarly enhanced PKG activity and reduced pathological hypertrophy/fibrosis and cardiac dysfunction after TAC. However, SIL failed to protect the heart in PKG1αC42S, unlike BAY, which activated PKG and thereby facilitated protective effects. This corresponded with minimal PDE5 activation in PKG1αC42S TAC versus higher activity in controls, and little colocalization of PDE5 with PKG1αC42S (versus co-localization with PKG1αWT) in stressed myocytes. In the stressed heart and myocytes, PKG1α C42 disulfide formation contributes to PDE5 activation. This augments the pathological role of PDE5 and so in turn enhances the therapeutic impact from its inhibition. PKG1α oxidation does not change the benefits from sGC activation. This finding favors the use of sGC activators regardless of PKG1α oxidation, and may help guide precision therapy leveraging the cGMP/PKG pathway to treat heart disease.