Neurogranin regulates eNOS function and endothelial activation
Endothelial nitric oxide (NO) is a critical mediator of vascular function and vascular remodeling. NO is produced by endothelial nitric oxide synthase (eNOS), which is activated by calcium (Ca2+)-dependent and Ca2+-independent pathways. Here, we report that neurogranin (Ng), which regulates Ca2+-cal...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720301919 |
| _version_ | 1818870538924195840 |
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| author | Vino T. Cheriyan Mabruka Alfaidi Ashton N. Jorgensen Md Ashiqul Alam Chowdhury S. Abdullah Gopi K. Kolluru Md Shenuarin Bhuiyan Christopher G. Kevil A. Wayne Orr Hyung W. Nam |
| author_facet | Vino T. Cheriyan Mabruka Alfaidi Ashton N. Jorgensen Md Ashiqul Alam Chowdhury S. Abdullah Gopi K. Kolluru Md Shenuarin Bhuiyan Christopher G. Kevil A. Wayne Orr Hyung W. Nam |
| author_sort | Vino T. Cheriyan |
| collection | DOAJ |
| description | Endothelial nitric oxide (NO) is a critical mediator of vascular function and vascular remodeling. NO is produced by endothelial nitric oxide synthase (eNOS), which is activated by calcium (Ca2+)-dependent and Ca2+-independent pathways. Here, we report that neurogranin (Ng), which regulates Ca2+-calmodulin (CaM) signaling in the brain, is uniquely expressed in endothelial cells (EC) of human and mouse vasculature, and is also required for eNOS regulation. To test the role of Ng in eNOS activation, Ng knockdown in human aortic endothelial cells (HAEC) was performed using Ng SiRNA along with Ng knockout (Ng −/−) in mice. Depletion of Ng expression decreased eNOS activity in HAEC and NO production in mice. We show that Ng expression was decreased by short-term laminar flow and long-them oscillating flow shear stress, and that Ng siRNA with shear stress decreased eNOS expression as well as eNOS phosphorylation at S1177. We further reveled that lack of Ng expression decreases both AKT-dependent eNOS phosphorylation, NF-κB-mediated eNOS expression, and promotes endothelial activation. Our findings also indicate that Ng modulates Ca2+-dependent calcineurin (CaN) activity, which suppresses Ca2+-independent AKT-dependent eNOS signaling. Moreover, deletion of Ng in mice also reduced eNOS activity and caused endothelial dysfunction in flow-mediated dilation experiments. Our results demonstrate that Ng plays a crucial role in Ca2+-CaM-dependent eNOS regulation and contributes to vascular remodeling, which is important for the pathophysiology of cardiovascular disease. |
| first_indexed | 2024-12-19T12:08:37Z |
| format | Article |
| id | doaj.art-6510083d3fd440a9a26fc1b8867dea9e |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-19T12:08:37Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-6510083d3fd440a9a26fc1b8867dea9e2022-12-21T20:22:17ZengElsevierRedox Biology2213-23172020-07-0134101487Neurogranin regulates eNOS function and endothelial activationVino T. Cheriyan0Mabruka Alfaidi1Ashton N. Jorgensen2Md Ashiqul Alam3Chowdhury S. Abdullah4Gopi K. Kolluru5Md Shenuarin Bhuiyan6Christopher G. Kevil7A. Wayne Orr8Hyung W. Nam9Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USADepartment of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA; Corresponding author. Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71103, USA.Endothelial nitric oxide (NO) is a critical mediator of vascular function and vascular remodeling. NO is produced by endothelial nitric oxide synthase (eNOS), which is activated by calcium (Ca2+)-dependent and Ca2+-independent pathways. Here, we report that neurogranin (Ng), which regulates Ca2+-calmodulin (CaM) signaling in the brain, is uniquely expressed in endothelial cells (EC) of human and mouse vasculature, and is also required for eNOS regulation. To test the role of Ng in eNOS activation, Ng knockdown in human aortic endothelial cells (HAEC) was performed using Ng SiRNA along with Ng knockout (Ng −/−) in mice. Depletion of Ng expression decreased eNOS activity in HAEC and NO production in mice. We show that Ng expression was decreased by short-term laminar flow and long-them oscillating flow shear stress, and that Ng siRNA with shear stress decreased eNOS expression as well as eNOS phosphorylation at S1177. We further reveled that lack of Ng expression decreases both AKT-dependent eNOS phosphorylation, NF-κB-mediated eNOS expression, and promotes endothelial activation. Our findings also indicate that Ng modulates Ca2+-dependent calcineurin (CaN) activity, which suppresses Ca2+-independent AKT-dependent eNOS signaling. Moreover, deletion of Ng in mice also reduced eNOS activity and caused endothelial dysfunction in flow-mediated dilation experiments. Our results demonstrate that Ng plays a crucial role in Ca2+-CaM-dependent eNOS regulation and contributes to vascular remodeling, which is important for the pathophysiology of cardiovascular disease.http://www.sciencedirect.com/science/article/pii/S2213231720301919Oxidative stressNitric oxideEndothelial dysfunctionNeurograninShear stressFlow-mediated dilation |
| spellingShingle | Vino T. Cheriyan Mabruka Alfaidi Ashton N. Jorgensen Md Ashiqul Alam Chowdhury S. Abdullah Gopi K. Kolluru Md Shenuarin Bhuiyan Christopher G. Kevil A. Wayne Orr Hyung W. Nam Neurogranin regulates eNOS function and endothelial activation Redox Biology Oxidative stress Nitric oxide Endothelial dysfunction Neurogranin Shear stress Flow-mediated dilation |
| title | Neurogranin regulates eNOS function and endothelial activation |
| title_full | Neurogranin regulates eNOS function and endothelial activation |
| title_fullStr | Neurogranin regulates eNOS function and endothelial activation |
| title_full_unstemmed | Neurogranin regulates eNOS function and endothelial activation |
| title_short | Neurogranin regulates eNOS function and endothelial activation |
| title_sort | neurogranin regulates enos function and endothelial activation |
| topic | Oxidative stress Nitric oxide Endothelial dysfunction Neurogranin Shear stress Flow-mediated dilation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720301919 |
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