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.
Highlights
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]
Detection of ZMPSTE24, Lamin A/C and Progerin mRNA in Human Blood Samples
We found an association between the inflammation biomarker hs-CRP and the expression of ZMPSTE24 mRNA
Summary
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]. 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 Following the the farnesylation of cysteine sulfhydryl, AAX is proteolytically cleaved by the. Ras-converting farnesylation of cysteine sulfhydryl, AAX is proteolytically cleaved by the Ras-convertingenzyme enzyme (RCE1)
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