Pin1 as a Protector of Vascular Endothelial Homeostasis
2011; Lippincott Williams & Wilkins; Volume: 59; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.111.186742
ISSN1524-4563
Autores Tópico(s)Biochemical and Molecular Research
ResumoHomeHypertensionVol. 59, No. 2Pin1 as a Protector of Vascular Endothelial Homeostasis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPin1 as a Protector of Vascular Endothelial Homeostasis Adnan Erol Adnan ErolAdnan Erol Originally published12 Dec 2011https://doi.org/10.1161/HYPERTENSIONAHA.111.186742Hypertension. 2012;59:e14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 To the Editor:In their recently published article in Hypertension, Chiasson and colleagues,1 in contrast to Ruan et al,2 demonstrated that binding of Pin1 to endothelial NO synthase (eNOS) facilitates the dephosphorylation and activation of the enzyme. Thus, the activated eNOS increases NO production, leading to endothelium-dependent dilatation and blood pressure regulation.1 Although there seems an implication that Pin1 directly results in serine-116 dephosphorylation of eNOS, they clearly showed that Pin1 deficiency negatively affects eNOS-regulated endothelial functions. However, in an editorial commentary for this study published in the same issue,3 the authors consider Pin1 as a phosphatase. In addition, they accentuate this mistake clearly in their Figure. Furthermore, they state that the findings of this study are consistent with the previous study done by Ruan et al,2 in contrast to the emphasis of Chiasson et al1 in their article.Pin1 is the only peptidyl-prolyl cis/trans-isomerase that specifically recognizes phosphorylated proline-directed serine/threonine peptide sequences.4 In other words, Pin1 can only bind to the phosphorylated proline-directed serine/threonine motifs of target proteins and just catalyzes the prolyl isomerization, leading a conformational change in the protein. If Pin1 catalyzes a cis- to trans-isomer change at the proline bond, it makes this target protein ideal substrate for protein phosphatases PP2A and PP2B.4,5 Altogether, Pin1 does not dephosphorylate, it just facilitates the dephosphorylating action of those phosphatases.In addition to these conflicting issues, Chiasson et al1 have not demonstrated how Pin1 facilitates dephosphorylation of eNOS on serine-116, which causes NO increase and improves endothelial function. Here, I propose a working model to clarify the uncertainty. eNOS is a Ca2+/calmodulin-dependent enzyme, the activity of which is influenced by the phosphorylation at ≥3 sites in the enzyme: serine-1177, threonine-495, and serine-116. Akt and the AMP-activated protein kinase are the important regulators of eNOS serine-1177. The phosphorylation of threonine-495 is modulated by the agonist bradykinin, and phosphorylation of eNOS at serine-116 is subjected to hemodynamic shear stress.5 Vascular endothelial growth factor (VEGF), one of the key activators of eNOS in the vessel wall, promotes the activation of enzyme through the dephosphorylation of eNOS at serine-116 by inducing the activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase (PP2B).5 On the other hand, Pin1 induces transcriptional upregulation of vascular endothelial growth factor.6 Taken together, Pin1-mediated increased activation of VEGF may result in dephosphorylation and activation of eNOS at serine-116. Thus, whereas Pin1 deficiency negatively influences endothelial function as demonstrated by Chiasson et al,1 deficiency of this important isomerase could also lead to the attenuation of VEGF-mediated angiogenesis (Figure).Download figureDownload PowerPointFigure. Pin1 upregulates the expression of vascular endothelial growth factor (VEGF) that, in turn, activates the phosphatase PP2B. Increased VEGF influence in the vessel wall and dephosphorylation of endothelial NO synthase (eNOS) at serine-116 (S116) by PP2B activates eNOS toward to the protection of endothelial homeostasis.Adnan Erol Erol Project Development House for the Disorders of Energy Metabolism Silivri-Istanbul, TurkeyDisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.References1. Chiasson VL, Munshi N, Chatterjee P, Young KJ, Mitchell BM. Pin1 deficiency causes endothelial dysfunction and hypertension. Hypertension. 2011; 58:431–438.LinkGoogle Scholar2. Ruan L, Torres CM, Qian J, Chen F, Mintz JD, Stepp DW, Fulton D, Venema RC. Pin1 prolyl isomerase regulates endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2011; 31:392–398.LinkGoogle Scholar3. Johnson AW, Faraci FM. Trans-forming endothelial nitric oxide synthase in hypertension: more than meets the eye. Hypertension. 2011; 58:359–360.LinkGoogle Scholar4. Lu KP, Zhou XZ. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation and signalling and disease. Nat Rev Mol Cell Biol. 2007; 8:904–916.CrossrefMedlineGoogle Scholar5. Kou R, Greif D, Michel T. Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor: implications for the vascular responses to cyclosporin A. J Biol Chem. 2002; 277:29669–29673.CrossrefMedlineGoogle Scholar6. Kim MR, Choi HS, Heo TH, Hwang SW, Kang KW. Induction of vascular endothelial growth factor by peptidyl-prolyl isomerase Pin1 in breast cancer cells. Biochem Biophys Res Commun. 2008; 369:547–553.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fagiani F, Vlachou M, Di Marino D, Canobbio I, Romagnoli A, Racchi M, Govoni S and Lanni C (2021) Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases, Cells, 10.3390/cells10123287, 10:12, (3287) Wang J, Liu G, Li Z and Wang X (2016) Pin1 in cardiovascular dysfunction: A potential double-edge role, International Journal of Cardiology, 10.1016/j.ijcard.2016.03.181, 212, (280-283), Online publication date: 1-Jun-2016. Perrucci G, Gowran A, Zanobini M, Capogrossi M, Pompilio G and Nigro P (2015) Peptidyl-prolyl isomerases: a full cast of critical actors in cardiovascular diseases, Cardiovascular Research, 10.1093/cvr/cvv096, 106:3, (353-364), Online publication date: 1-Jun-2015., Online publication date: 1-Jun-2015. Wang J, Zhu W, Xu Z, Du W, Zhang H, Sun X and Wang X (2014) Pin1, endothelial nitric oxide synthase, and amyloid-β form a feedback signaling loop involved in the pathogenesis of Alzheimer's disease, hypertension, and cerebral amyloid angiopathy, Medical Hypotheses, 10.1016/j.mehy.2013.11.023, 82:2, (145-150), Online publication date: 1-Feb-2014. Wang J, Li S, Li Y, Zhang Y, Zhang T, Zhao C, Yao C and Du L (2013) Could Pin1 help us conquer essential hypertension at an earlier stage? A promising early-diagnostic biomarker and its therapeutic implications for the disease, Medical Hypotheses, 10.1016/j.mehy.2013.08.020, 81:5, (931-935), Online publication date: 1-Nov-2013. Johnson A and Faraci F (2011) Response to Pin1 as a Protector of Vascular Endothelial Homeostasis, Hypertension, 59:2, (e15-e15), Online publication date: 1-Feb-2012. February 2012Vol 59, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.111.186742PMID: 22158642 Originally publishedDecember 12, 2011 PDF download Advertisement SubjectsCell Biology/Structural BiologyCell Signaling/Signal TransductionEndothelium/Vascular Type/Nitric OxideEtiologyHypertensionMechanismsPathophysiology
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