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ZMPSTE24 Is Associated with Elevated Inflammation and Progerin Mrna

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ZMPSTE24 Is Associated with Elevated Inflammation and Progerin Mrna cells Article ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA 1, 1, 1 2 Moritz Messner y, Santhosh Kumar Ghadge y, Thomas Maurer , Michael Graber , Simon Staggl 1, Sarah Christine Maier 3, Gerhard Pölzl 1 and Marc-Michael Zaruba 1,* 1 Department of Internal Medicine III, Cardiology and Angiology, Medical University Innsbruck, 6020 Innsbruck, Austria; [email protected] (M.M.); [email protected] (S.K.G.); [email protected] (T.M.); [email protected] (S.S.); [email protected] (G.P.) 2 Department of Thoracic & Cardiac Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria; [email protected] 3 Department of Medical Statistics, Informatics and Health Economics, Medical University Innsbruck, 6020 Innsbruck, Austria; [email protected] * Correspondence: [email protected]; Tel.: +0043-512-504-25621 Moritz Messner and Santhosh Kumar Ghadge contributed equally to this manuscript. y Received: 30 March 2020; Accepted: 27 August 2020; Published: 28 August 2020 Abstract: Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A—also called progerin—causes Hutchinson–Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-CRP). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-CRP. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-CRP protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; p = 0.0004) and lnlamin A/C (n = 110; r = 0.82, p < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-CRP with lnZMPSTE24 (n = 110; r = 0.21; p = 0.01) and lnlamin A/C (n = 110; r = 0.24; p = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging. Keywords: ZMPSTE24; lamin A/C; progerin; aging; inflammation 1. Introduction Nuclear lamins are structural proteins and as type V intermediate filaments involved in major functions like cell-cycle regulation, DNA-replication, signal transduction and gene expression, as well as chromatin and pore positioning [1]. Defects while processing lamin A could lead to the premature aging syndrome Hutchinson–Gilford progeria (HGPS) [2]. Individuals suffering from HGPS die as a result of severe atherosclerosis, either fatal stroke, myocardial infarction or heart failure generally before the age of 20 [3]. To process mature lamin A from its precursor, prelamin A, four post-translational modifications are necessary (Figure1): In the first step, the C-terminal CAAX motif (C = cysteine sulfhydryl, Cells 2020, 9, 1981; doi:10.3390/cells9091981 www.mdpi.com/journal/cells Cells 2020, 9, x FOR PEER REVIEW 2 of 10 Cells 2020, 9, 1981 2 of 10 To process mature lamin A from its precursor, prelamin A, four post-translational modifications are necessary (Figure 1): In the first step, the C-terminal CAAX motif (C = cysteine sulfhydryl, A = Aaliphatic= aliphatic amino amino acid, acid, X X== aminoamino acid acid other other than proline) isis farnesylatedfarnesylated [4[4].]. FollowingFollowing thethe farnesylationfarnesylation ofof cysteinecysteine sulfhydryl,sulfhydryl, AAXAAX isis proteolyticallyproteolytically cleavedcleaved byby thethe Ras-converting Ras-converting enzymeenzyme (RCE1)(RCE1) or or zinc–metalloproteinase zinc–metalloproteinase 24 24 (ZMPSTE (ZMPSTE 24) 24) (Step (Step 2), 2), and and in in Step Step 3 3 the the remaining remaining farnesylated farnesylated cysteinecysteine undergoesundergoes carboxylcarboxyl methylationmethylation throughthrough isoprenylcysteineisoprenylcysteine carboxylcarboxyl methylmethyl transferasetransferase (ICMT).(ICMT). AfterAfter thethe processprocess ofof farnesylation,farnesylation, laminslamins areare targetedtargeted toto thethe nucleus,nucleus, wherewhere theythey interactinteract withwith thethe innerinner nuclearnuclear membrane.membrane. AA finalfinal cleavagecleavage (Step(Step 4)4) byby ZMPSTEZMPSTE 2424 isis fundamentalfundamental toto formform functionalfunctional lamin lamin A A [ 5[5,6].,6]. FigureFigure 1.1. LaminLamin A A biogenesis biogenesis consists consists of fo ofur four steps steps of post-translational of post-translational processing. processing. In Step In 1 to Step 3 the 1 toC-terminal 3 the C-terminal CAAX motiv CAAX is motivprocessed is processed by farnesyl by farnesyltransferase transferase (FT), ras-converting (FT), ras-converting enzyme (RCE1) enzyme or (RCE1)zinc-metalloproteinase or zinc-metalloproteinase 24 (ZMPSTE 24 (ZMPSTE 24) and isopre 24) andnylcysteine isoprenylcysteine carboxyl carboxyl methyl transferase methyl transferase (ICMT). (ICMT).In the final In the step final the step farnesyl the farnesyl anchor anchor is cleaved is cleaved by ZMPSTE24 by ZMPSTE24 to form to formmature mature lamin lamin A protein. A protein. The Thepoint-mutation point-mutation LMNA LMNA 1824 1824 C > C T,> G608GT, G608G in exon in exon 11 11activates activates a cryptic a cryptic splicing splicing site site which which results results in ina atruncated truncated prelamin prelamin A A protein protein (Δ (D5050 aa) aa) also also called called progerin progerin lacking the cleavage sitesite forfor ZMPSTE24.ZMPSTE24. InIn patients patients with with HGPS, HGPS, ZMPSTE24 ZMPSTE24 is is unable unable to tocleave cleavethe thefarnesylated farnesylated and andcarboxyl carboxylmethylated methylated residueresidue leading leading to to accumulation accumulation of of the the truncatedtruncated prematurepremature proteinprotein progerin progerin in in thethe nuclearnuclear peripheryperiphery disablingdisabling its its fixation fixation into into the the nuclearnuclear lamina.lamina. AsAs aa consequenceconsequence nucleinuclei areare morphologicallymorphologically misshapedmisshaped andand itsits proper functioning functioning is is severely severely impaired impaired [7]. [7 The]. The cause cause for HGPS for HGPS is most is mostprevalently prevalently a point- a point-mutationmutation in the in lamin the lamin A gene A gene leading leading to a to frameshift a frameshift which which results results in in a a protein protein lacking thethe cleavagecleavage sitesite forfor ZMPSTE24 ZMPSTE24 [ 8[8].]. MutationsMutations causingcausing anan enzymeenzyme dysfunctiondysfunction inin ZMPSTE24ZMPSTE24 alsoalso resultresult inin HGPS HGPS relatedrelated premature premature aging aging disorders disorders like like mandibuloacral–dysplasiamandibuloacral–dysplasia typetype BB andand restrictiverestrictive dermopathy.dermopathy. ExpressionExpression of of low low levels levels of of progerin progerin through through alternative alternative splicing splicing was was found found in non in HGPSnon HGPS cells andcells wasand previously was previously linked linked by Sca ffibydi Scaffidi et al. with et al. physiologic with physiologic aging [7]. aging Consecutively, [7]. Consecutively, progerin is progerin discussed is bydiscussed various by groups various as agroups marker as for a marker cardiovascular for cardiovascular aging. Since aging. laminopathies Since laminopathies are a known are causea known of cardiomyopathies,cause of cardiomyopathies, we recently we found recently a positive found correlation a positive between correlation progerin between mRNA progerin expression mRNA and LVexpression dysfunction and in LV patients dysfunction with dilated in patients cardiomyopathy with dilated [9]. cardiomyopathy Furthermore, we [9]. previously Furthermore, found anwe associationpreviously offound obesity an andassociation inflammation of obesity (hs-CRP) and inflammation with high levels (hs-CRP) of progerin with mRNAhigh levels expression of progerin [10]. mRNATherefore, expression we aimed[10]. to elucidate correlations of ZMPSTE24, lamin A/C and progerin mRNA expressionTherefore, with thewe inflammatoryaimed to elucidate marker correlations CRP. of ZMPSTE24, lamin A/C and progerin mRNA expression with the inflammatory marker CRP. 2. Materials and Methods 2.1. Study Population We performed a cross-sectional retrospective analysis enrolling patients presenting at our cardiology outpatient clinic between 2014 and 2016. We consecutively included 110 Caucasian Cells 2020, 9, 1981 3 of 10 Cells 2020, 9, x FOR PEER REVIEW 3 of 10 patients over 18 years of age of both sexes. Diagnoses of heart failure etiology are depicted in Table A1. Most of the2. Materials patients and su ffMethodsered from DCM, followed by ICM, hypertrophic cardiomyopathy and other reasons for heart failure [10]. 2.1. Study Population For measurement of ZMPSTE24, lamin A/C and progerin mRNA levels, EDTA blood samples were obtainedWe from performed 110 patients. a cross-sectional retrospective analysis enrolling patients presenting at our cardiology outpatient
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