Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
Compound
Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Background Arginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase ( eNOS ). We tested the hypotheses that arginase II activity participates in the regulation of Ca
2+
/Ca
2+
/
calmodulin-dependent kinase II
/ eNOS activation, and this process is dependent on mitochondrial p32. Methods and Results Downregulation of arginase II increased the concentration of cytosolic Ca
2+
([Ca
2+
]c) and decreased mitochondrial Ca
2+
([Ca
2+
]m) in microscopic and fluorescence-activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca
2+
/Ca
2+
/
calmodulin-dependent kinase II
. These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca
2+
from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II -null mice resulted in reduced
p32 protein
level. In the aortas of wild-type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO -dependent vasorelaxation. Arginase activity,
p32 protein
expression, spermine amount, and [Ca
2+
]m were increased in the aortas from apolipoprotein E (ApoE
-/-
) mice fed a high-cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca
2+
/Ca
2+
/
calmodulin-dependent kinase II
-dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice. Conclusions These data demonstrate a novel function of arginase II in regulation of Ca
2+
-dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.
...
PMID:Arginase II Contributes to the Ca
2+
/CaMKII/eNOS Axis by Regulating Ca
2+
Concentration Between the Cytosol and Mitochondria in a p32-Dependent Manner. 3037 Dec 3
Although arginase II (ArgII) is abundant in mitochondria, Ca
2+
-accumulating organelles, the relationship between ArgII activity and Ca
2+
translocation into mitochondria and the regulation of cytosolic Ca
2+
signaling are completely unknown. We investigated the effects of ArgII activity on mitochondrial Ca
2+
uptake through mitochondrial
p32 protein
(p32m) and on
CaMKII
-dependent vascular smooth muscle cell (VSMC) contraction. Native low-density lipoprotein stimulation induced an increase in [Ca
2+
]m as measured by CoCl
2
-quenched calcein-AM fluorescence, which was prevented by Arg inhibition in hAoSMCs and reduced in mAoSMCs from ArgII
-/-
mice. Conversely, [Ca
2+
]c analyzed with Fluo-4 AM was increased by Arg inhibition and ArgII gene knockout. The increased [Ca
2+
]c resulted in
CaMKII
and MLC 20 phosphorylation, which was associated with enhanced vasoconstriction activity to phenylephrine (PE) in the vascular tension assay. Cy5-tagged siRNA against mitochondrial p32 mRNA (sip32m) abolished mitochondrial Ca
2+
uptake and induced activation of
CaMKII
. Spermine, a polyamine, induced mitochondrial Ca
2+
uptake and dephosphorylation of
CaMKII
and was completely inhibited by sip32m incubation. In mAoSMCs from ApoE-null mice fed a high-cholesterol diet (ApoE
-/-
+HCD), Arg activity was increased, and spermine concentration was higher than that of wild-type mice. Furthermore, [Ca
2+
]m and p32m levels were elevated, and
CaMKII
phosphorylation was reduced in mAoSMCs from ApoE
-/-
+HCD. In vascular tension experiments, an attenuated response to vasoconstrictors in de-endothelialized aorta from ApoE
-/-
+HCD was recovered by incubation of sip32m. ArgII activity-dependent production of spermine augments Ca
2+
transition from the cytosol to the mitochondria in a p32m-dependent manner and regulates
CaMKII
-dependent constriction in VSMCs.
...
PMID:Arginase II activity regulates cytosolic Ca
2+
level in a p32-dependent manner that contributes to Ca
2+
-dependent vasoconstriction in native low-density lipoprotein-stimulated vascular smooth muscle cells. 3115 12
