Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3',5'-Monophosphate-Dependent Protein Kinase I
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Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3',5'-Monophosphate-Dependent Protein Kinase I. / Kamynina, Alisa; Guttzeit, Sebastian; Eaton, Philip; Cuello, Friederike.
In: HYPERTENSION, Vol. 79, No. 5, 2022, p. 946-956.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3',5'-Monophosphate-Dependent Protein Kinase I
AU - Kamynina, Alisa
AU - Guttzeit, Sebastian
AU - Eaton, Philip
AU - Cuello, Friederike
PY - 2022
Y1 - 2022
N2 - Background:We 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.Methods:To 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.Results:Knock-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.Conclusions:Oxidation 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.
AB - Background:We 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.Methods:To 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.Results:Knock-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.Conclusions:Oxidation 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.
U2 - 10.1161/HYPERTENSIONAHA.122.18756
DO - 10.1161/HYPERTENSIONAHA.122.18756
M3 - SCORING: Journal article
VL - 79
SP - 946
EP - 956
JO - HYPERTENSION
JF - HYPERTENSION
SN - 0194-911X
IS - 5
ER -