Olivier Le Saux, Ph.D.

Associate Professor of Cell and Molecular Biology

John A. Burns School of Medicine

University of Hawaii at Manoa

651 Ilalo St, Room 222

Honolulu HI 96813

Email: lesaux@hawaii.edu



Websites:


- https://sites.google.com/site/ccrheart/research/le-saux-lab

- PubMed Link


Education


Ph.D., 1997, Université d’Aix-Marseille I, Marseille, France

MS, 1992, Université d’Aix-Marseille I, Marseille, France

BS, 1989, Université d’Aix-Marseille I, Marseille, France


RESEARCH INTERESTS


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.


PXE and Beta-thalassemia

We studied the calcification associated with sickle cell anemia and β-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. Using a mouse model of β-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 β-thalassemia leading to abnormal calcification of connective tissues.


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 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.


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) and myocardial ischemia following left coronary ligation.


Research rotations will provide the opportunity to work with graduate students and postdoctoral fellows, and to gain expertise in the following methodologies:


Immunohistochemistry, Immunofluorescence, histology, qPCR, Western blotting and mouse work.



RECENT PUBLICATIONS:


V. Douet, M.B. Heller and O. Le Saux. DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter to the mouse Abcc6 promoter and governs its. Biochem. Biophys. Res. Com. 2007, 354:66-71. (20 citations)


O. Le Saux, K. Teeters, S. Miyasato, J. Choi, G. Nakamatsu, J. A. Richardson, B. Starcher, E. C. Davis, E. K. Tam, C. Jourdan-Le Saux. The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties. Am. J. Physiol., Lung Cell. Mol. Physiol. 2008 295:1007-1017. (1 citations)


L. Martin, V. Douet, C.M. VanWart, M.B. Heller, and O. Le Saux. A Mouse Model of -thalassemia shows a liver-specific downregulation of Abcc6 expression. Am. J. Pathol.  2011, 178:774–783.


C. Brampton, Y. Yamaguchi, O. Vanakker, Lut van Laer, L. Chen, M Thakore, A. De Paepe, V. Pomozi, P.T. Szabo, A. Varadi and O. Le Saux. Vitamin K does not prevent soft tissue mineralization in a mouse model of pseudoxanthoma elasticum. Cell Cycle. 2011, Vol 10 (11) June 1. In Press.


G. Lefthériotis, P. Abraham, P-H. Ducluzeau, Y. Le Corre, O. Le Saux, D. Henrion, F. Prunier and L. Martin, MD-PhD. Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum. Journal of Vascular Surgery. In press.


G. Leftheriotis, O. Vanakker, O. Le Saux, L. Martin. Letter to the Editor in response to the article of C. Markello et al 2011 entitled "Vascular pathology of medial arterial calcifications in NT5E deficiency: Implications for the role of adenosine in pseudoxanthoma elasticum". Molecular Genetics and Metabolism, In Press.

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