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 Erdmann, Jeannette Erdfdi, Heribert Schunkert, Zalán Szabó, András Váradi, Olivier Le Saux

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9 Citations (Scopus)

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)159-70
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
Publication statusPublished - Jan 2014

Keywords

  • ATP-Binding Cassette Transporters
  • Animals
  • Blotting, Western
  • Calcinosis
  • Calcium-Binding Proteins
  • Disease Models, Animal
  • Extracellular Matrix Proteins
  • Heart Injuries
  • Humans
  • Immunohistochemistry
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Multidrug Resistance-Associated Proteins
  • Myocardial Ischemia
  • Osteopontin
  • Real-Time Polymerase Chain Reaction

Cite this

Brampton, Christopher ; Aherrahrou, Zouhair ; Chen, Li-Hsieh ; Martin, Ludovic ; Bergen, Arthur A B ; Gorgels, Theo G M F ; Erdmann, Jeannette ; Erdfdi, Jeannette ; Schunkert, Heribert ; Szabó, Zalán ; Váradi, András ; 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. 159-70.
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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.",
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author = "Christopher Brampton and Zouhair Aherrahrou and Li-Hsieh Chen and Ludovic Martin and Bergen, {Arthur A B} and Gorgels, {Theo G M F} and Jeannette Erdmann and Jeannette Erdfdi and Heribert Schunkert and Zal{\'a}n Szab{\'o} and Andr{\'a}s V{\'a}radi and {Le Saux}, Olivier",
year = "2014",
month = "1",
doi = "10.1016/j.ajpath.2013.09.015",
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Brampton, C, Aherrahrou, Z, Chen, L-H, Martin, L, Bergen, AAB, Gorgels, TGMF, Erdmann, J, 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. 159-70. 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; Erdmann, Jeannette; Erdfdi, Jeannette; Schunkert, Heribert; Szabó, Zalán; Váradi, András; Le Saux, Olivier.

In: American Journal of Pathology, Vol. 184, No. 1, 01.2014, p. 159-70.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury

AU - Brampton, Christopher

AU - Aherrahrou, Zouhair

AU - Chen, Li-Hsieh

AU - Martin, Ludovic

AU - Bergen, Arthur A B

AU - Gorgels, Theo G M F

AU - Erdmann, Jeannette

AU - Erdfdi, Jeannette

AU - Schunkert, Heribert

AU - Szabó, Zalán

AU - Váradi, András

AU - Le Saux, Olivier

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters

KW - Animals

KW - Blotting, Western

KW - Calcinosis

KW - Calcium-Binding Proteins

KW - Disease Models, Animal

KW - Extracellular Matrix Proteins

KW - Heart Injuries

KW - Humans

KW - Immunohistochemistry

KW - Liver

KW - Mice

KW - Mice, Inbred C57BL

KW - Multidrug Resistance-Associated Proteins

KW - Myocardial Ischemia

KW - Osteopontin

KW - Real-Time Polymerase Chain Reaction

U2 - 10.1016/j.ajpath.2013.09.015

DO - 10.1016/j.ajpath.2013.09.015

M3 - Article

C2 - 24479134

VL - 184

SP - 159

EP - 170

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 1

ER -