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

Agbor, Larry N; Nair, Anand; Wu, Jing; Lu, Ko Ting; Davis, Deborah R.; Keen, Henry L.; Quelle, Frederick W.; McCormick, James A.; Singer, Jeffrey D.

doi:10.1172/jci.insight.129793

Cited by 24 publications

(16 citation statements)

References 63 publications

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“…Moreover, CUL3-KLHL25 is a part of the biggest ubiquitin ligase Cullin-Ring family and is involved in the regulation of numerous biological processes, such as cell cycle regulation, DNA damage responses, and cell apoptosis ( Davidge et al, 2019 ; Genschik et al, 2013 ). The lack of CUL3 has been associated with defects in embryogenesis, hypertension, diminished angiogenesis, progressive interstitial inflammation, exacerbated colonic inflammation, and swelled spleens and lymph nodes ( Agbor et al, 2019 ; Li et al, 2017 ; Maekawa et al, 2017 ; Mathew et al, 2012 ; Saritas et al, 2019 ; Singer et al, 1999 ). Interestingly, some of these defects, for example, progressive interstitial inflammation, exacerbated colonic inflammation, and swelled spleens and lymph nodes, are clearly relevant to immune system imbalance.…”

Section: Discussionmentioning

confidence: 99%

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

Tian

Hao

Jin

et al. 2021

eLife

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Inducible regulatory T (iTreg) cells play a central role in immune suppression. As iTreg cells are differentiated from activated T (Th0) cells, cell metabolism undergoes dramatic changes, including a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). Although the reprogramming in fatty acid metabolism is critical, the mechanism regulating this process during iTreg differentiation is still unclear. Here we have revealed that the enzymatic activity of ATP-citrate lyase (ACLY) declined significantly during iTreg differentiation upon transforming growth factor β1 (TGFβ1) stimulation. This reduction was due to CUL3-KLHL25-mediated ACLY ubiquitination and degradation. As a consequence, malonyl-CoA, a metabolic intermediate in FAS that is capable of inhibiting the rate-limiting enzyme in FAO, carnitine palmitoyltransferase 1 (CPT1), was decreased. Therefore, ACLY ubiquitination and degradation facilitate FAO and thereby iTreg differentiation. Together, we suggest TGFβ1-CUL3-KLHL25-ACLY axis as an important means regulating iTreg differentiation and bring insights into the maintenance of immune homeostasis for the prevention of immune diseases.

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Section: Discussionmentioning

confidence: 99%

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

Tian

Hao

Jin

et al. 2021

eLife

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“…Increased medial wall thickness and proliferation of VSM cells were considered to be associated with the pathogenesis of hypertension (14). We observed morphometric changes in the vasculature under PE by HE, Masson, and IF staining.…”

Section: Downregulation Of Crl3 Function and The Accumulation Of Wnk mentioning

confidence: 93%

“…Rho-related BTB domain containing protein 1 (RhoBTB1) serves as adaptor of CUL3 for degradation of phosphodiesterase 5 (PDE5), which promotes the cyclic 3 ′ ,5 ′ -monophosphatedependent relaxation of VSMCs (12). Moreover, conditional genetic ablation of CUL3 causes the accumulation of RhoA, a small GTPase modulating Rho kinase (ROCK) activity in VSM, and promotes vasoconstriction (11,13,14). Recently, Zeniya et al reported that Kelch-like 2 (KLHL2), a Kelch-like family member expressed in VSM, mediates ubiquitination of With-No-lysine(K) kinase 3 (WNK3) for CRL3 degradation (15).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Cullin 3 Ligase Signaling Pathways Contributes to Hypertension in Preeclampsia

Zhang

Jiang

Zhang

2021

Front. Cardiovasc. Med.

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Background: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality; however, its etiology and pathophysiology remain obscure. PE is initiated by inadequate spiral artery remodeling and subsequent placental ischemia/hypoxia, which stimulates release of bioactive factors into maternal circulation, leading to hypertension and renal damage.Methods and Results: Abundance of key components of cullin 3-ring ubiquitin ligase (CRL3), including cullin 3 (CUL3) and its neddylated modification, and adaptors including Kelch-like 2 (KLHL2) and Rho-related BTB domain containing protein 1 was all decreased in spiral arteries and placentas of PE patients. Similar changes were found in aortic tissues and renal distal tubules of pregnant mice treated with Nω-nitro-l-arginine methyl ester hydrochloride. The downregulation of CRL3 function led to accumulation of with-no-lysine kinases, phosphodiesterase 5, and RhoA in vessels and renal distal tubules, which promoted vasoconstriction and Na–Cl cotransporter activation in the distal convoluted tubule (DCT), as well as vascular and DCT structure remodeling. Proton pump inhibitor esomeprazole partially restored CRL3 function. In vitro studies have shown that increased abundance of JAB1, a component of the COP9 signalosome, inhibited CUL3 neddylation and promoted the expression of hypoxia-inducible factor 1α, which downregulated peroxisome proliferator–activated receptor γ and further promoted CUL3 inactivation. KLHL3/2 was degraded by increased autophagy.Conclusion: These findings support that the downregulation of CRL3 function disrupts the balance of vasoconstriction and vasodilation and aggravates excess reabsorption of sodium in PE.

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“…The authors further demonstrated that the mechanisms linking the mutation in SMC-PPARγ and hypertension is critically involved in Cullin-3. In SMC, RhoA and phosphodiesterase 5 are substrates for CRL3 ( 29 , 31 ) and either the loss-of-function mutation or the deletion of Cullin-3 in SMC caused severe hypertension and vascular dysfunction with increased RhoA kinase and decreased nitric oxide (NO) sensitivity ( 32 , 33 ). Another study revealed that mice expressing DN PPARγ in SMC exhibited augmented hypertension and vascular remodeling caused by deoxycorticosterone acetate-salt ( 34 ).…”

Section: Smc-pparγ and Vascular Remodeling/dysfunctionmentioning

confidence: 99%

Anti-inflammatory mechanisms of the vascular smooth muscle PPARγ

Mukohda

Ozaki

2021

J Smooth Muscle Res

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This review highlights molecular mechanisms of anti-inflammatory and protective effects of the nuclear transcription factor, peroxisome proliferator-activated receptor γ (PPARγ) in vascular tissue. PPARγ is an ubiquitously expressed nuclear factor, and well-studied in adipose tissue and inflammatory cells. Additionally, beneficial effects of vascular PPARγ’s on atherosclerosis and vascular remodeling/dysfunction have been reported although the detailed mechanism remains to be completely elucidated. Clinical and basic studies have shown that the synthetic PPARγ ligands, thiazolidinediones (TZDs), have protective effects against cardiovascular diseases such as atherosclerosis. Recent studies utilizing genetic tools suggested that those protective effects of TZDs on cardiovascular diseases are not due to a consequence of improvement of insulin resistance, but may be due to a direct effect on PPARγ’s in vascular endothelial and smooth muscle cells. In this review, we discuss proposed mechanisms by which the vascular PPARγ regulates vascular inflammation and remodeling/dysfunction especially in smooth muscle cells.

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

Cited by 24 publications

References 63 publications

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

Downregulation of Cullin 3 Ligase Signaling Pathways Contributes to Hypertension in Preeclampsia

Anti-inflammatory mechanisms of the vascular smooth muscle PPARγ

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