The complicated problem of efficient stimulation of elastic fiber production in already developed human tissues has not yet been solved. The present study introduces sodium ascorbate (SA) as a stimulator of elastogenesis in cultures of different cell types including fibroblasts isolated from patients with elastopathy genetic diseases. We then elucidated mechanisms of elastogenic action of SA. SA exercises its net elastogenic effect only after being actively transported into the cell interior through two separate mechanisms. These are the “fast effect,” which reflects the greater stability of intracellular tropoelastin, and the “late effect,” which reflects the true enhancement of the elastin gene expression occurring after SA-induced activation of c-src tyrosine kinase and the consecutive phosphorylation of IGF-1 receptor, which triggers the downstream signals leading to activation of the elastin gene expression. In conclusion, for the first time we have established that SA is a potent stimulator of elastic fiber production.

The complicated problem of efficient stimulation of elastic fiber production in already developed human tissues has not yet been solved. The present study introduces sodium ascorbate (SA) as a stimulator of elastogenesis in cultures of different cell types including fibroblasts isolated from patients with elastopathy genetic diseases. We then elucidated mechanisms of elastogenic action of SA. SA exercises its net elastogenic effect only after being actively transported into the cell interior through two separate mechanisms. These are the “fast effect,” which reflects the greater stability of intracellular tropoelastin, and the “late effect,” which reflects the true enhancement of the elastin gene expression occurring after SA-induced activation of c-src tyrosine kinase and the consecutive phosphorylation of IGF-1 receptor, which triggers the downstream signals leading to activation of the elastin gene expression. In conclusion, for the first time we have established that SA is a potent stimulator of elastic fiber production.

Approximately 7000 rare disorders exist, affecting 2 percent of Canadians and millions of people worldwide. Given that for many rare diseases only one allele is mutated, we hypothesize inducing expression of the remaining wild-type allele may have a therapeutic effect. SMAD3 heterozygosity results in Aneurysms-Osteoarthritis Syndrome (AOS) – an aortic aneurysm disorder also known as Loeys-Dietz Syndrome Type 3. We conducted a screen of FDA-approved compounds and found that 13-cis-retinoic acid (13-CRA) induces SMAD3 in normal human fibroblast cultures. Treatment with therapeutic concentrations of 13-CRA increased SMAD3 mRNA in normal human fibroblasts, patient fibroblasts, wild-type murine vascular smooth muscle cells and Smad3+/- murine vascular smooth muscle cells. Increases in SMAD3 protein were also observed in normal human fibroblasts, patient fibroblasts, and wild-type murine vascular smooth muscle cells. Immunofluorescent imaging revealed the primary site of protein induction to be nuclear. We report here the in vitro induction of SMAD3 mRNA and protein by therapeutic levels of 13-CRA and suggest further investigation of this modality for the treatment of AOS.