The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury

Christopher Brampton, Zouhair Aherrahrou, Li Hsieh Chen, Ludovic Martin, Arthur A B Bergen, Theo G M F Gorgels, Jeannette Erdfdi, Heribert Schunkert, Z. Szabó, A. Váradi, Olivier Le Saux

Research output: Contribution to journalArticle

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Abstract

Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6-/- mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/- mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.

Original languageEnglish
Pages (from-to)159-170
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
Publication statusPublished - Jan 2014

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Osteopontin
Liver
Wounds and Injuries
Osteocalcin
Hydrodynamics
Genetic Therapy
Infarction
Ligation
Blood Vessels
Tail
Hepatocytes
Veins
Coronary Vessels
Calcium
Morbidity
Injections
Survival
matrix Gla protein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Brampton, C., Aherrahrou, Z., Chen, L. H., Martin, L., Bergen, A. A. B., Gorgels, T. G. M. F., ... Le Saux, O. (2014). The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. American Journal of Pathology, 184(1), 159-170. https://doi.org/10.1016/j.ajpath.2013.09.015

The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. / Brampton, Christopher; Aherrahrou, Zouhair; Chen, Li Hsieh; Martin, Ludovic; Bergen, Arthur A B; Gorgels, Theo G M F; Erdfdi, Jeannette; Schunkert, Heribert; Szabó, Z.; Váradi, A.; Le Saux, Olivier.

In: American Journal of Pathology, Vol. 184, No. 1, 01.2014, p. 159-170.

Research output: Contribution to journalArticle

Brampton, C, Aherrahrou, Z, Chen, LH, Martin, L, Bergen, AAB, Gorgels, TGMF, Erdfdi, J, Schunkert, H, Szabó, Z, Váradi, A & Le Saux, O 2014, 'The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury', American Journal of Pathology, vol. 184, no. 1, pp. 159-170. https://doi.org/10.1016/j.ajpath.2013.09.015
Brampton, Christopher ; Aherrahrou, Zouhair ; Chen, Li Hsieh ; Martin, Ludovic ; Bergen, Arthur A B ; Gorgels, Theo G M F ; Erdfdi, Jeannette ; Schunkert, Heribert ; Szabó, Z. ; Váradi, A. ; Le Saux, Olivier. / The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. In: American Journal of Pathology. 2014 ; Vol. 184, No. 1. pp. 159-170.
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