Le Saux Lab

Le Saux Lab 

Our laboratory investigates how the ABCC6 gene that encodes a transmembrane transporter, influences ectopic calcifications in cardiac and vascular tissues.


Olivier Le Saux, Ph.D. (Assistant Professor)
Christopher Brampton, Ph.D. (Post-Doctoral Fellow)

Current Research

Calcification of cardiovascular tissues occurs in a variety of pathological conditions, including vascular injury, renal failure, diabetes mellitus, atherosclerosis, and aging. Mineralization is multifactorial and results from abormal changes in the balance between activators and inhibitors of calcification. We and others have established a link between ABCC6 and the chronic calcification of pseudoxanthoma elasticum (PXE) in human and the dystrophic cardiac calcification phenotype (DCC) in mice. ABCC6 is primarily expressed in liver and the kidneys but not in connective tissues. Therefore, we use various mice models to elucidate the characteristics of this novel mineralization inhibitor pathway.

1. PXE and Beta-thalassemia

We studied the calcification associated with sickle cell anemia and b-thalassemia, which are very similar to PXE, in collaboration with the University of Modena (Italy) and the Hospital of Angers (France). We first established that the mineralization in these hemoglobinopathies arise independently of ABCC6 mutations (Hamlin et al, 2003, Br. J. Hematol., 122:852-854). Using a mouse model of b-thalassemia, we found that the synthesis of ABCC6 is significantly decreased in liver but not in kidneys and is mediated by the transcription factor NF-E2. We predicted that a similar mechanism also occurs in human patients with b-thalassemia leading to abnormal calcification of connective tissues. (Martin et al, Am. J. Pathol, in press).

The liver ABCC6 expression is decreased in a 
beta-thalassemia mouse model over time
(click on image to enlarge)

2. ABCC6 structure and Function

As part of another collaborative work with the Hungarian Academy of Sciences in Budapest, we characterized the structural and functional consequences of ABCC6 pathologic mutations. We showed that the ABCC6 protein is an ATP-dependent active transporter and that PXE-causing mutations in ABCC6 result in proteins with impaired transport characteristics (Ilias et al, 2002, J. Biol. Chem. 277: 16860-67) and also altered protein folding, glycosylation and intracellular trafficking. We have recently identified an FDA-approved compound (sodium 4-phenylbutyrate) that effectively correct the defects caused by PXE mutations thus opening the door to potential therapy for patients with ABCC6 mutations. (Le Saux et al, manuscript Submitted).

Transient expression of PXE-causing ABCC6 mutants in mouse live
(click on image to enlarge)

3. Acute cardiovascular calcification 

We also use ABCC6-null mice to study the molecular pathways that lead to exacerbated cardiac and arterial calcification after freeze-thaw injuries (DCC phenotype) as well as left coronary ligation to analyze the levels of calcification regulators in affected tissues (Brampton et al, manuscript in preparation).

Myocardium calcification in ABCC6-/- mice following cryoinjuries
(click on image to enlarge)

  Contact Information

  Dr. Olivier Le Saux
  Assistant Professor
  Phone: 808-692-1504
  Fax: 808-692-1970