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The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway 2023 年沃尔特-B-坎农奖讲座:PPARγ-RhoBTB1-CUL3 通路调节血管功能和血压的机制
Function Pub Date : 2024-01-05 DOI: 10.1093/function/zqad071
Curt D Sigmund
{"title":"The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway","authors":"Curt D Sigmund","doi":"10.1093/function/zqad071","DOIUrl":"https://doi.org/10.1093/function/zqad071","url":null,"abstract":"\u0000 Human genetic clinical trial data suggest that PPARγ, a nuclear receptor transcription factor plays an important role in the regulation of arterial blood pressure. The examination of a series of novel animal models, coupled with transcriptomic and proteomic analysis has reveal that PPARγ and its target genes employ diverse pathways to regulate vascular function and blood pressure. In endothelium, PPARγ target genes promote an antioxidant state, stimulating both nitric oxide (NO) synthesis and bioavailability, essential components of endothelial—smooth muscle communication. In vascular smooth muscle, PPARγ induces the expression of a number of genes which promote an anti-inflammatory state and tightly control the level of cGMP thus promoting responsiveness to endothelial derived NO. One of the PPARγ targets in smooth muscle, RhoBTB1 acts as a substrate adaptor for proteins to be ubiquitinated by the E3 ubiquitin ligase Cullin-3 and targeted for proteasomal degradation. One of these proteins, phosphodiesterase 5 (PDE5) is a target of the CUL3/RhoBTB1 pathway. PDE5 degrades cGMP to GMP and thus regulates the smooth muscle response to NO. Moreover, expression of RhoBTB1 under condition of RhoBTB1-deficiency reverses established arterial stiffness. In conclusion, the coordinated action of PPARγ in endothelium and smooth muscle is needed to maintain NO bioavailability and activity, and is an essential regulator of vasodilator/vasoconstrictor balance and regulates blood vessel structure and stiffness.","PeriodicalId":503843,"journal":{"name":"Function","volume":"27 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139383136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Need for Inspiration and Admiration 需要激励和钦佩
Function Pub Date : 2024-01-03 DOI: 10.1093/function/zqae001
Ole H Petersen
{"title":"The Need for Inspiration and Admiration","authors":"Ole H Petersen","doi":"10.1093/function/zqae001","DOIUrl":"https://doi.org/10.1093/function/zqae001","url":null,"abstract":"","PeriodicalId":503843,"journal":{"name":"Function","volume":"139 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function POMC 神经元 BBSome 对体重的调节与其纤毛功能无关
Function Pub Date : 2023-12-23 DOI: 10.1093/function/zqad070
D. Guo, Paul A Williams, Connor Laule, Charles Seaby, Qihong Zhang, V. Sheffield, Kamal Rahmouni
{"title":"POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function","authors":"D. Guo, Paul A Williams, Connor Laule, Charles Seaby, Qihong Zhang, V. Sheffield, Kamal Rahmouni","doi":"10.1093/function/zqad070","DOIUrl":"https://doi.org/10.1093/function/zqad070","url":null,"abstract":"The BBSome, a complex of several Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as a critical regulator of energy homeostasis. Although the BBSome is best known for its involvement in cilia trafficking, through a process that involve BBS3, it also regulates the localization of cell membrane receptors underlying metabolic regulation. Here, we show that inducible Bbs1 gene deletion selectively in proopiomelanocortin (POMC) neurons cause a gradual increase in body weight which was associated with higher fat mass. In contrast, inducible deletion of Bbs3 gene in POMC neurons failed to affect body weight and adiposity. Interestingly, loss of BBS1 in POMC neurons led to glucose intolerance and insulin insensitivity, whereas BBS3 deficiency in these neurons is associated with slight impairment in glucose handling, but normal insulin sensitivity. BBS1 deficiency altered the plasma membrane localization of serotonin 5-HT2C receptor (5-HT2CR) and ciliary trafficking of neuropeptide Y2 receptor (NPY2R). On the other hand, BBS3 deficiency which disrupted the ciliary localization of the BBSome did not interfere with plasma membrane expression of 5-HT2CR, but reduced the trafficking of NPY2R to cilia. We also show that deficiency in BBS1, but not BBS3, alters mitochondria dynamics associated with decreased total and phosphorylated levels of dynamin-like protein 1 (DRP1) protein. Importantly, rescuing DRP1 activity restored mitochondria dynamics and localization of 5-HT2CR and NPY2R in BBS1 deficient cells. The contrasting effects on energy and glucose homeostasis evoked by POMC neuron deletion of BBS1 versus BBS3 indicate that BBSome regulation of metabolism is not related to its ciliary function in these neurons.","PeriodicalId":503843,"journal":{"name":"Function","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139161902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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