Hypertension and Vascular Inflammation

HomeHypertensionVol. 77, No. 1Hypertension and Vascular Inflammation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBHypertension InflammationAnother Piece of the Genetic Puzzle Dan Pugh, Neeraj Dhaun PughDan Pugh University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University Edinburgh, United Kingdom. Search more papers by this author , DhaunNeeraj Correspondence to: Dhaun, 47 Little France Crescent, EH16 4TJ, Scotland, Email E-mail Address: [email protected] Originally published8 Dec 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.16420Hypertension. 2021;77:190–192This article is a commentary on followingChromosome 2 Fragment Substitutions in Dahl Salt-Sensitive Rats RNA Sequencing Identified Enpep Hs2st1 as Inflammatory ModulatorsHypertension common. It affects one-third adult population leading cause premature death loss disability-adjusted life years.1 Hypertension major risk factor coronary heart disease, chronic kidney stroke, peripheral vascular disease. goal antihypertensive treatment limit such devastating organ injury, thereby reducing morbidity mortality. Mechanisms underlying development progression hypertension are poorly understood but involve complex interplay between key pathophysiological pathways—kidney dysfunction, sympathetic overdrive, increased tone, immune system activation—and environmental changes high salt, low potassium intake. A large number drugs available that act these different biological pathways. Unfortunately, recent US data suggest estimated proportion adults with controlled decreased from 53.8% 2013 2014 43.7% 2017 2018,2 an associated rise hypertension-related cardiovascular This may be partly due relevant mechanisms being inadequately targeted various available, counter-regulatory triggered treatments diminishing their blood pressure (BP)-lowering effect. Thus, newer approaches urgently needed.See related article, pp 178–189There has been growing interest role inflammation maintenance hypertension. Similarly, genetic predisposition apparent,3 it factors govern inflammatory response involved hypertensive injury. discovery specific implicated loci allow clinicians identify individuals at significant developing pave way earlier, intervention. Moreover, mechanistic understanding susceptibility might leveraged therapeutic advantage.The salt-sensitive (SS) rat, generated Lewis Kitchener over half century ago, genetically susceptible aggravated high-salt diet long history identifying fundamental translate improved human health. For example, 1960s 1970s, was used show formula milk designed use resulted SS rat mortality content baby food.4 Following publication study, Senate did further work which mandate lowering salt foods. In another classic cross-transplanting kidneys rats salt-resistant counterparts elegantly demonstrated critical regulation BP.5 Using linkage analysis, studies have compared genome other inbred strains potentially influence BP.The study Berillo et al,6 published edition Journal, advances our knowledge about influences inflammation. Previous same group consomic approach chromosome normotensive, Brown Norway reduced BP when transferred rat.7 current takes observations aimed genes responsible protective effects. To do this, authors created congenic species introgression middle distal portions into (S2Ba: mid-portion 2; S2Bb; portion Figure). These were then fed normal- (NSD HSD), determined.Download figureDownload PowerPointFigure. al6 Journal describes one method isolating culprit loci. As can seen example APA inhibitors, future novel agents. indicates aminopeptidase A; BN, Norway; BP, pressure; HSD, diet; NSD, normal-salt SS, sensitive.Compared rats, lower both S2Ba (distal portion) S2Bb (middle under higher HSD. locus generation HSD conditions found 2. inflammation, however, greater rats. findings mediating diets could within becomes focus remainder study. RNA-seq quantitative polymerase chain reaction differentially expressed region, they find downregulation upregulation They conclude downregulated anti-inflammatory NSD upregulated proinflammatory suggesting potential each modulation inflammation.Enpep encodes integral membrane protein, glutamyl aminopeptidase, also known (aminopeptidase A). increase cleaving N-terminal aspartate angiotensin II converting III. Angiotensin III main effector renin-angiotensin brain where acts raise through activation nervous system, inhibition baroreflex nucleus tractus solitarius, vasopressin release. timely. Firibastat first-in-class inhibitor APA. recently phase examined 8 weeks firibastat 256 overweight or obese patients hypertension.8 investigators lowered systolic office ≈10 mm Hg diastolic ≈4 Hg. Based encouraging data, 3 Treatment-resistant will examine benefits resistant top treatment.9 Given beneficial effects mediated diuresis would interesting setting, fluid homeostasis problematic, commonplace.The gene member heparan sulfate biosynthetic enzyme family transfers 2-position iduronic acid residue sulfate. knockout mice characterized renal agenesis. Whether not HS2ST1 play man less apparent although artery disease.10Where next research? Here, focused aorta examining roles resistance vessels, arguably important interesting. Additionally, model used, baseline so does necessarily reflect clinical situation normotensive individual gradually develops progresses time affect multiple organs. models organs, eye, brain, heart, kidney, important. Interestingly, others shown Enpep, its protein APA, widely kidney. However, appears renoprotective role, least setting II-mediated hypertension, injurious than wild-type counterparts.11 case prescription beta adrenergic blockers failure, depend timing.The maps out effective strategy determining paves many targets.AffiliationSources FundingD. funded Chief Scientist Office PhD Fellowship (CAF/19/01); N. Senior Clinical (SCAF/19/02).DisclosuresNone.FootnotesThe opinions those American Heart Association.For Disclosures, see page 192.Correspondence bean.[email protected]ac.ukReferences1. Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, Alexander Estep K, Hassen Abate Akinyemiju TF, al.. Global burden 110 115 Hg, 1990-2015.JAMA. 2017; 317:165–182. doi: 10.1001/jama.2016.19043CrossrefMedlineGoogle Scholar2. Muntner Hardy ST, Fine LJ, Jaeger BC, Wozniak G, Levitan EB, Colantonio LD. Trends control among 1999-2000 2017-2018.JAMA. 2020; 324:1190–1200. 10.1001/jama.2020.14545CrossrefMedlineGoogle Scholar3. 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Efficacy safety firibastat, inhibitor, ethnic origins.Circulation. 2019; 140:138–146. 10.1161/CIRCULATIONAHA.119.040070LinkGoogle Scholar9. ClinicalTrials.gov. (FRESH).https://clinicaltrials.gov/ct2/show/NCT04277884. Accessed November 4, 2020.Google Scholar10. LeBlanc Zuber V, Andreassen BK, Witoelar Zeng Bettella Wang Y, McEvoy Thompson WK, Schork AJ, al.; CARDIoGRAM Consortium. Identifying variants disease shared several factors.Circ 2016; 118:83–94. 10.1161/CIRCRESAHA.115.306629LinkGoogle Scholar11. Velez JCQ, Arif E, Rodgers J, Hicks MP, Arthur JM, Nihalani Bruner ET, Budisavljevic MN, Atkinson Fitzgibbon WR, Deficiency angiotensinase increases glomerular injury.J Am Nephrol. 28:2119–2132. 10.1681/ASN.2016111166CrossrefMedlineGoogle Scholar Back Next FiguresReferencesRelatedDetailsRelated articlesChromosome ModulatorsOlga Berillo, al. Hypertension. 2021;77:178-189 January 2021Vol Issue 1Article InformationMetrics Download: 109 © 2020 Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.16420PMID: 33296247 publishedDecember 8, PDF download SubjectsInflammation