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  Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation

Jin, Y.-J., Chennupati, R., Li, R., Liang, G., Wang, S., Iring, A., et al. (2021). Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation. JOURNAL OF CLINICAL INVESTIGATION, 131(21): e145734. doi:10.1172/JCI145734.

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Jin, Young-June1, Author              
Chennupati, Ramesh1, Author              
Li, Rui1, Author              
Liang, Guozheng1, Author              
Wang, ShengPeng1, Author              
Iring, Andras1, Author              
Graumann, Johannes2, Author              
Wettschureck, Nina1, Author              
Offermanns, Stefan1, Author              
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              
2Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591705              

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 Abstract: 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 G(q)/G(11)-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.

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 Dates: 2021-11-01
 Publication Status: Published online
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 Identifiers: ISI: 000715042800002
DOI: 10.1172/JCI145734
PMID: 34499618
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Title: JOURNAL OF CLINICAL INVESTIGATION
Source Genre: Journal
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Pages: - Volume / Issue: 131 (21) Sequence Number: e145734 Start / End Page: - Identifier: ISSN: 0021-9738