Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects

Autor: Shriram Nallamshetty, Jorge Plutzky, Jiaohua Chen, Masanori Aikawa, Peter Libby, Shinji Goto, Elena Aikawa, Jochen D. Muehlschlegel, Maximillian A. Rogers, Tan Pham
Rok vydání: 2020
Předmět:
0301 basic medicine
Receptors
Retinoic Acid
medicine.drug_class
Cellular differentiation
Myocytes
Smooth Muscle
Cell
Heart Valve Diseases
Retinoic acid
Tretinoin
030204 cardiovascular system & hematology
Muscle
Smooth
Vascular
Article
Retinoids
03 medical and health sciences
chemistry.chemical_compound
Ectopic calcification
0302 clinical medicine
Osteogenesis
medicine
Humans
Retinoid
Cholesterol 7-alpha-Hydroxylase
Isotretinoin
Vascular Calcification
Cells
Cultured
Apolipoprotein C-III
Extracellular Matrix Proteins
Chemistry
Calcium-Binding Proteins
Alkaline Phosphatase
medicine.disease
Coronary Vessels
Cell biology
Carotid Arteries
030104 developmental biology
medicine.anatomical_structure
Nuclear receptor
Aortic Valve
Carrier Proteins
Cardiology and Cardiovascular Medicine
Signal Transduction
Calcification
medicine.drug
Zdroj: Arterioscler Thromb Vasc Biol
ISSN: 1524-4636
1079-5642
DOI: 10.1161/atvbaha.119.313366
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: