Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling

Background: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake...

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Main Authors: Vinaiphat, Arada, Pazhanchamy, Kalailingam, JebaMercy, Gnanasekaran, Ngan, SoFong Cam, Leow, Melvin Khee-Shing, Ho, Hee Hwa, Gao, Yong-Gui, Lim, Kah-Leong, Richards, A. Mark, de Kleijn, Dominique P. V., Chen, Christopher P., Kalaria, Raj N., Liu, Jian, O'Leary, Deborah D., McCarthy, Neil E., Sze, Siu Kwan
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/174605
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-174605
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Cardiovascular disease
Endothelial cell
spellingShingle Medicine, Health and Life Sciences
Cardiovascular disease
Endothelial cell
Vinaiphat, Arada
Pazhanchamy, Kalailingam
JebaMercy, Gnanasekaran
Ngan, SoFong Cam
Leow, Melvin Khee-Shing
Ho, Hee Hwa
Gao, Yong-Gui
Lim, Kah-Leong
Richards, A. Mark
de Kleijn, Dominique P. V.
Chen, Christopher P.
Kalaria, Raj N.
Liu, Jian
O'Leary, Deborah D.
McCarthy, Neil E.
Sze, Siu Kwan
Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
description Background: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach. Methods: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation. Results: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart. Conclusions: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Vinaiphat, Arada
Pazhanchamy, Kalailingam
JebaMercy, Gnanasekaran
Ngan, SoFong Cam
Leow, Melvin Khee-Shing
Ho, Hee Hwa
Gao, Yong-Gui
Lim, Kah-Leong
Richards, A. Mark
de Kleijn, Dominique P. V.
Chen, Christopher P.
Kalaria, Raj N.
Liu, Jian
O'Leary, Deborah D.
McCarthy, Neil E.
Sze, Siu Kwan
format Article
author Vinaiphat, Arada
Pazhanchamy, Kalailingam
JebaMercy, Gnanasekaran
Ngan, SoFong Cam
Leow, Melvin Khee-Shing
Ho, Hee Hwa
Gao, Yong-Gui
Lim, Kah-Leong
Richards, A. Mark
de Kleijn, Dominique P. V.
Chen, Christopher P.
Kalaria, Raj N.
Liu, Jian
O'Leary, Deborah D.
McCarthy, Neil E.
Sze, Siu Kwan
author_sort Vinaiphat, Arada
title Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
title_short Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
title_full Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
title_fullStr Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
title_full_unstemmed Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
title_sort endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling
publishDate 2024
url https://hdl.handle.net/10356/174605
_version_ 1795375092599881728
spelling sg-ntu-dr.10356-1746052024-04-03T07:27:54Z Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling Vinaiphat, Arada Pazhanchamy, Kalailingam JebaMercy, Gnanasekaran Ngan, SoFong Cam Leow, Melvin Khee-Shing Ho, Hee Hwa Gao, Yong-Gui Lim, Kah-Leong Richards, A. Mark de Kleijn, Dominique P. V. Chen, Christopher P. Kalaria, Raj N. Liu, Jian O'Leary, Deborah D. McCarthy, Neil E. Sze, Siu Kwan Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Tan Tock Seng Hospital Medicine, Health and Life Sciences Cardiovascular disease Endothelial cell Background: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach. Methods: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation. Results: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart. Conclusions: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions. Ministry of Education (MOE) National Medical Research Council (NMRC) This work was supported in part by the Singapore National Medical Research Council (NMRC/OFIRG/0003/2016 to S. Kwan Sze and K.L. Lim), Singapore Ministry of Education (MOE Tier 1 RG21/21 to S. Kwan Sze and Y.-G. Gao), Canadian Institutes of Health Research Tier 1 Canada Research Chair (to S. Kwan Sze), and a start-up research grant from Brock University (to S. Kwan Sze). 2024-04-03T07:27:54Z 2024-04-03T07:27:54Z 2023 Journal Article Vinaiphat, A., Pazhanchamy, K., JebaMercy, G., Ngan, S. C., Leow, M. K., Ho, H. H., Gao, Y., Lim, K., Richards, A. M., de Kleijn, D. P. V., Chen, C. P., Kalaria, R. N., Liu, J., O'Leary, D. D., McCarthy, N. E. & Sze, S. K. (2023). Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling. Arteriosclerosis, Thrombosis, and Vascular Biology, 43(3), 427-442. https://dx.doi.org/10.1161/ATVBAHA.122.318439 1079-5642 https://hdl.handle.net/10356/174605 10.1161/ATVBAHA.122.318439 36700429 2-s2.0-85148678246 3 43 427 442 en NMRC/OFIRG/0003/2016 RG21/21 Arteriosclerosis, Thrombosis, and Vascular Biology © 2023 American Heart Association, Inc. All rights reserved.