Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3',5'-Monophosphate-Dependent Protein Kinase I.
Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3',5'-Monophosphate-Dependent Protein Kinase I.
复制标题
硝酰基供体 CXL-1020 通过靶向环鸟苷-3,5-单磷酸依赖性蛋白激酶 I 中的 C195 来降低血压。
DOI：
10.1161/hypertensionaha.122.18756
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Kamynina A
中科院分区：
文献类型：
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作者：
Kamynina A
我们之前已经证明，硝基引起血管舒张，至少部分是通过诱导C117和C195在PKGI（环鸟苷单磷酸依赖蛋白激酶I）的高亲和力环鸟苷单磷酸结合位点形成二硫内键。本研究的目的是确定硝基供体是否通过这种新的PKGI激活机制在体内降低血压。为了确定这一点，我们建立了C195S PKGI敲入小鼠模型，该模型普遍表达一种突变激酶，可抵抗硝基诱导的二硫化物内活化。结果敲入型和野生型仔鼠在外观、体重、PKGI蛋白表达和血气含量方面均无差异。除了敲入动物的盲肠显著增大外，基因型之间的器官重量相似。通过无线电遥测在体内监测24小时内的平均动脉压和心率，在基线和血管紧张素ii诱导的高血压或败血症期间，基因型之间没有显着差异。临床相关的硝基供体CXL-1020对血压正常的动物没有降低血压作用。相比之下，给高血压野生型小鼠服用CXL-1020可使其血压降低10±4 mm Hg (P=0.0184)，而敲入小鼠则不受影响。结论C195在PKGI中的氧化作用与硝基供体的降压作用有关，强调了硝基供体在环磷酸鸟苷水平降低且不足以激活PKGI的病理情况下的潜在重要性。
BackgroundWe previously demonstrated that nitroxyl causes vasodilation, at least in part, by inducing the formation of an intradisulfide bond between C117 and C195 in the high affinity cyclic guanosine monophosphate-binding site of PKGI (cyclic guanosine monophosphate-dependent protein kinase I). The aim of this study was to determine whether nitroxyl donors lower blood pressure via this novel PKGI activation mechanism in vivo.MethodsTo determine this, a C195S PKGI knock-in mouse model was generated that ubiquitously and constitutively expresses a mutant kinase resistant to nitroxyl-induced intradisulfide activation.ResultsKnock-in and wild-type littermates did not differ in appearance, body weight, in PKGI protein expression or blood gas content. Organ weight was similar between genotypes apart from the cecum that was significantly enlarged in knock-in animals. Mean arterial pressure and heart rate monitored in vivo over 24 hours by radio-telemetry revealed neither a significant difference between genotypes at baseline nor during angiotensin II–induced hypertension or sepsis. CXL-1020, a clinically relevant nitroxyl donor, did not lower blood pressure in normotensive animals. In contrast, administering CXL-1020 to hypertensive wild-type mice reduced their blood pressure by 10±4 mm Hg (P=0.0184), whereas the knock-in littermates were unaffected.ConclusionsOxidation of C195 in PKGI contributes to the antihypertensive effects observed in response to nitroxyl donors, emphasising the potential importance of nitroxyl donors in pathological scenarios when cyclic guanosine monophosphate levels are reduced and insufficient to activate PKGI.