Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation
Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.
| Errataetall: |
CommentIn: J Clin Invest. 2021 Nov 1;131(21):. - PMID 34720094 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:131 |
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| Enthalten in: |
The Journal of clinical investigation - 131(2021), 21 vom: 01. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jin, Young-June [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.12.2021 Date Revised 02.02.2022 published: Print CommentIn: J Clin Invest. 2021 Nov 1;131(21):. - PMID 34720094 Citation Status MEDLINE |
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| doi: |
10.1172/JCI145734 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330418742 |
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| 100 | 1 | |a Jin, Young-June |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 07.12.2021 | ||
| 500 | |a Date Revised 02.02.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: J Clin Invest. 2021 Nov 1;131(21):. - PMID 34720094 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cell Biology | |
| 650 | 4 | |a Endothelial cells | |
| 650 | 4 | |a Hypertension | |
| 650 | 4 | |a Nitric oxide | |
| 650 | 4 | |a Vascular Biology | |
| 650 | 7 | |a NOS3 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase Type III |2 NLM | |
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| 650 | 7 | |a Protein Kinase C |2 NLM | |
| 650 | 7 | |a EC 2.7.11.13 |2 NLM | |
| 700 | 1 | |a Chennupati, Ramesh |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Guozheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, ShengPeng |e verfasserin |4 aut | |
| 700 | 1 | |a Iring, András |e verfasserin |4 aut | |
| 700 | 1 | |a Graumann, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Wettschureck, Nina |e verfasserin |4 aut | |
| 700 | 1 | |a Offermanns, Stefan |e verfasserin |4 aut | |
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