Maximillian A Rogers1, Jiaohua Chen2, Shriram Nallamshetty2, Tan Pham1, Shinji Goto1, Jochen D Muehlschlegel3, Peter Libby2, Masanori Aikawa1,2, Elena Aikawa1,2, Jorge Plutzky1,2,4. 1. From the Division of Cardiovascular Medicine, Center for Interdisciplinary Cardiovascular Sciences (M.A.R., T.P., S.G., M.A., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 2. Division of Cardiovascular Medicine, Center for Excellence in Vascular Biology (J.C., S.N., P.L., M.A., E.A., J.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 3. Department of Anesthesiology, Perioperative and Pain Medicine (J.D.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 4. Preventive Cardiology (J.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Abstract
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.
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 humancardiovascular 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 humancardiovascular 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-cisRA, 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 humancardiovascular 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.
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