RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity

Mukohda, Masashi; Fang, Shi; Wu, Jing; Agbor, Larry N; Nair, Anand; Ibeawuchi, Stella‐Rita; Hu, Chunyan; Liu, Xuebo; Lu, Ko‐Ting; Guo, Deng‐Fu; Davis, Deborah R.; Keen, Henry L.; Quelle, Frederick W.

doi:10.1172/jci123462

Cited by 35 publications

(39 citation statements)

References 57 publications

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“…Conversely, the cullin 3 substrate adapter RhoBTB1 protects from arterial stiffness and hypertension through its ubiquitylation and the consequent degradation of the phosphodiesterase PDE5. Lower amounts of PDE5 lead to increased cGMP levels, which in turn promotes smooth muscle cell relaxation (Mukohda et al, 2019). This important role for cullin 3 in vascular smooth muscle cells is in good agreement with its degradation of RhoB in ECs, which also limits contraction and preserves endothelial integrity (Kovacěvicé t al., 2018;Sakaue et al, 2017).…”

Section: Ubiquitin-dependent Modifications In Vascular Diseasementioning

confidence: 65%

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Majolée

Kovačević

Hordijk

2019

Journal of Cell Science

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Endothelial cell-cell contacts are essential for vascular integrity and physiology, protecting tissues and organs from edema and uncontrolled invasion of inflammatory cells. The vascular endothelial barrier is dynamic, but its integrity is preserved through a tight control at different levels. Inflammatory cytokines and G-protein-coupled receptor agonists, such as histamine, reduce endothelial integrity and increase vascular leakage. This is due to elevated myosin-based contractility, in conjunction with phosphorylation of proteins at cell-cell contacts. Conversely, reducing contractility stabilizes or even increases endothelial junctional integrity. Rho GTPases are key regulators of such cytoskeletal dynamics and endothelial cell-cell contacts. In addition to signaling-induced regulation, the expression of junctional proteins, such as occludin, claudins and vascular endothelial cadherin, also controls endothelial barrier function. There is increasing evidence that, in addition to protein phosphorylation, ubiquitylation (also known as ubiquitination) is an important and dynamic post-translational modification that regulates Rho GTPases, junctional proteins and, consequently, endothelial barrier function. In this Review, we discuss the emerging role of ubiquitylation and deubiquitylation events in endothelial integrity and inflammation. The picture that emerges is one of increasing complexity, which is both fascinating and promising given the clinical relevance of vascular integrity in the control of inflammation, and of tissue and organ damage.

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Section: Ubiquitin-dependent Modifications In Vascular Diseasementioning

confidence: 65%

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Majolée

Kovačević

Hordijk

2019

Journal of Cell Science

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“…Another interpretation of these data could be that cGMP is produced but is rapidly degraded by PDE5, the main PDE involved in cGMP degradation in vascular smooth muscle cells. Indeed, we recently identified PDE5 as a CUL3 target (22). However, PDE5 expression was not increased but rather decreased in aorta of S-CUL3KO mice (data not shown).…”

Section: Discussionmentioning

confidence: 85%

“…BACURD1, another BTB domain-containing protein, is the substrate adaptor for RhoA (12). We identified another BTB domain-containing protein, RhoBTB1, as a PPARγ target gene in vascular smooth muscle that acts as a substrate adaptor for phosphodiesterase 5 (PDE5), a key protein regulating cGMP turnover (22). There are approximately 200 different BTB domain-containing proteins that may provide substrate specificity for a large number of protein substrates (23).…”

Section: Introductionmentioning

confidence: 99%

Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension

Agbor¹,

Nair²,

Wu³

et al. 2019

JCI Insight

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“…Importantly, studies have shown that mutations (P467L or V290M) in the ligand-binding domain of PPARγ cause not only insulin resistance but also early-onset hypertension [ 86 , 87 ], indicating its role in BP regulation. Moreover, dominant negative mice model of PPARγ (S-P467L) in VSMCs developed arterial stiffness and vascular dysfunction, accompanied by hypertension [ 88 , 89 ]. These results indicate that PPARγ in VSMCs may play an essential role in regulating BP.…”

Section: Role Of Ups In the Regulation Of Vascular Functionmentioning

confidence: 99%

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review

Hirohama

Ishizawa

Shibata

2020

IJMS

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The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes by regulating protein turnover in various tissues. Increasing evidence demonstrates the roles of UPS in blood pressure regulation. In the kidney, filtered sodium is reabsorbed through diverse sodium transporters and channels along renal tubules, and studies conducted till date have provided insights into the complex molecular network through which ubiquitin ligases modulate sodium transport in different segments. Components of these pathways include ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2, Cullin-3, and Kelch-like 3. Moreover, accumulating data indicate the roles of UPS in blood vessels, where it modulates nitric oxide bioavailability and vasoconstriction. Cullin-3 not only regulates renal salt reabsorption but also controls vascular tone using different adaptor proteins that target distinct substrates in vascular smooth muscle cells. In endothelial cells, UPS can also contribute to blood pressure regulation by modulating endothelial nitric oxide synthase. In this review, we summarize current knowledge regarding the role of UPS in blood pressure regulation, focusing on renal sodium reabsorption and vascular function.

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RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity

Cited by 35 publications

References 57 publications

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review

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