AIMS: Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects.METHODS AND RESULTS: LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27±0.07 vs. 1.59±0.04, P=0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35y) (1.34±0.08 vs. 1.64±0.08, P=0.019); moreover, LTL was shorter in statin-naive HeFH subjects as compared to controls (1.23±0.08 vs. 1.58±0.04, P=0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33±0.05 vs. 1.55±0.08, P=0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls.CONCLUSIONS: We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors / A. Baragetti, F. Bonacina, L. Da Dalt, A. Moregola, V. Zampoleri, F. Pellegatta, L. Grigore, A. Pirillo, R. Spina, A.B. Cefalù, M. Averna, G.D. Norata, A.L. Catapano. - In: EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY. - ISSN 2047-4873. - 29:5(2022 Mar), pp. zwaa115.721-zwaa115.729. [10.1093/eurjpc/zwaa115]

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

A. Baragetti
Primo
Conceptualization
;
F. Bonacina
Secondo
;
L. Da Dalt;A. Moregola;V. Zampoleri;F. Pellegatta;G.D. Norata
Penultimo
Conceptualization
;
A.L. Catapano
Ultimo
Conceptualization
2022-03

Abstract

AIMS: Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects.METHODS AND RESULTS: LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27±0.07 vs. 1.59±0.04, P=0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35y) (1.34±0.08 vs. 1.64±0.08, P=0.019); moreover, LTL was shorter in statin-naive HeFH subjects as compared to controls (1.23±0.08 vs. 1.58±0.04, P=0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33±0.05 vs. 1.55±0.08, P=0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls.CONCLUSIONS: We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.
CHD; Cellular ageing; Familial hypercholesterolaemia; Haematopoiesis; Telomeres
Settore BIO/14 - Farmacologia
Low density lipoprotein receptor (LDLR)-independent effects of proprotein convertase subtilisin/kexin type 9 (PCSK9): role in modulating insulin-resistance, ectopic fat accumulation and low-grade inflammation
Proprotein convertase subtilisin/kexin type 9 (PCSK9): a link between lipotoxicity, mitochondrial dysfunction, and frailty-associated heart failure
Integrating metabolism and immunity: cellular and molecular pathways leading to metabolic dysregulation and autoimmunity
Targeting epigenetic REPROGRamming of innate immune cells in Atherosclerosis Management and other chronic inflammatory diseases
17-nov-2020
https://academic.oup.com/eurjpc/article/29/5/721/5983847
Article (author)
File in questo prodotto:
File Dimensione Formato  
Baragetti A et al. Eur J Prev Cardiol 2020.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 657.56 kB
Formato Adobe PDF
657.56 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/831361
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 1
social impact