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Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator
Maximillian A Rogers1, Jiaohua Chen2, Shriram Nallamshetty2
1From 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.
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.
Insights
Retinoic acid (RA) regulates cardiovascular calcification by influencing cell differentiation. Acyclic retinoids, like peretinoin, show promise for treating calcification without adverse effects linked to cyclic retinoids.
Area of Science:
- Cardiovascular Biology
- Molecular Endocrinology
- Calcification Research
Background:
- Retinoic acid (RA) is a nuclear receptor ligand that controls gene transcription and cell differentiation.
- The role of RA in human ectopic calcification, particularly in cardiovascular diseases, remains largely unknown.
- Cardiovascular calcification contributes to atherosclerosis and heart valve disease.
Purpose of the Study:
- To investigate whether retinoic acid (RA) regulates osteogenic differentiation in human arterial smooth muscle cells and aortic valvular interstitial cells.
- To elucidate the mechanisms by which RA influences cardiovascular cell calcification.
- To compare the effects of cyclic and acyclic retinoids on cardiovascular calcification and potential side effects.
Main Methods:
- Human cardiovascular cells (smooth muscle cells and valvular interstitial cells) were cultured and treated with RA, RAR antagonists, or siRNA.
- Calcification assays were performed to quantify mineral deposition.
- Levels of key proteins (MGP) and enzyme activities (TNAP) involved in calcification were measured.
- Responses to cyclic retinoids (all-trans RA, 9-cis RA, 13-cis RA) and the acyclic retinoid peretinoin were compared.
- Osteoblast mineralization was assessed using human femur-derived osteoblasts.
Main Results:
- RA stimulation suppressed calcification in human cardiovascular cells.
- Inhibition of RA signaling (using AGN 193109 or RARα siRNA) increased calcification.
- RA treatment increased the expression of the calcification inhibitor MGP and decreased TNAP activity.
- The acyclic retinoid peretinoin suppressed cardiovascular cell calcification without adverse effects like APOC3 secretion or CYP7A1 downregulation.
- Unlike cyclic retinoids, peretinoin did not inhibit osteoblast mineralization.
Conclusions:
- Retinoids play a significant role in regulating human cardiovascular calcification.
- Selective retinoid modulators, such as acyclic retinoids, may offer a therapeutic strategy for cardiovascular calcification.
- Acyclic retinoids may provide a safer alternative to cyclic retinoids, avoiding detrimental effects on atherogenesis and gene expression.
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