OBJECTIVE: Retinoic acid (RA) is a ligand for nuclear receptors that modulate 
gene transcription and cell differentiation. Whether RA controls ectopic 
calcification in humans is unknown. We tested the hypothesis that RA regulates 
osteogenic differentiation of human arterial smooth muscle cells and aortic 
valvular interstitial cells that participate in atherosclerosis and heart valve 
disease, respectively. Approach and Results: Human cardiovascular tissue 
contains immunoreactive RAR (RA receptor)-a retinoid-activated nuclear receptor 
directing multiple transcriptional programs. RA stimulation suppressed primary 
human cardiovascular cell calcification while treatment with the RAR inhibitor 
AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in 
a coordinated manner, increasing levels of the calcification inhibitor MGP 
(matrix Gla protein) while decreasing calcification-promoting TNAP (tissue 
nonspecific alkaline phosphatase) activity. Given that nuclear receptor action 
varies as a function of distinct ligand structures, we compared calcification 
responses to cyclic retinoids and the acyclic retinoid peretinoin. Peretinoin 
suppressed human cardiovascular cell calcification without inducing either 
secretion of APOC3 (apolipoprotein-CIII), which promotes atherogenesis, or 
reducing CYP7A1 (cytochrome P450 family 7 subfamily A member 1) expression, 
which occurred with cyclic retinoids all-trans RA, 9-cis RA, and 13-cis RA. 
Additionally, peretinoin did not suppress human femur osteoblast mineralization, 
whereas all-trans RA inhibited osteoblast mineralization.
CONCLUSIONS: These results establish retinoid regulation of human cardiovascular 
calcification, provide new insight into mechanisms involved in these responses, 
and suggest selective retinoid modulators, like acyclic retinoids may allow for 
treating cardiovascular calcification without the adverse effects associated 
with cyclic retinoids.