Adenosine, Via A 2B Receptors, Inhibits Human (P-SMC) Progenitor Smooth Muscle Cell Growth
| Autor: | Ruth Stiller, Zaichuan Mi, J. Fingerle, Raghvendra K. Dubey, Marinella Rosselli, Bruno Imthurn, Brigitte Leeners, Delbert G. Gillespie, Isabella Baruscotti, Edwin K. Jackson |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Neointimal hyperplasia Neointima biology Chemistry Cyclin D Adenosine kinase 030204 cardiovascular system & hematology medicine.disease Adenosine Cell biology Adenylyl cyclase 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Adenosine deaminase Internal Medicine medicine biology.protein Protein kinase A medicine.drug |
| Zdroj: | Hypertension. 75:109-118 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.119.13698 |
| Popis: | c-Kit+ progenitor smooth muscle cells (P-SMCs) can develop into SMCs that contribute to injury-induced neointimal thickening. Here, we investigated whether adenosine reduces P-SMC migration and proliferation and whether this contributes to adenosine’s inhibitory actions on neointima formation. In human P-SMCs, 2-chloroadenosine (stable adenosine analogue) and BAY60-6583 (A 2B agonist) inhibited P-SMC proliferation and migration. Likewise, increasing endogenous adenosine by blocking adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl) adenine (inhibits adenosine deaminase) and 5-iodotubercidin (inhibits adenosine kinase) attenuated P-SMC proliferation and migration. Neither N 6 -cyclopentyladenosine (A 1 agonist), CGS21680 (A 2A agonist), nor N 6 -(3-iodobenzyl)-adenosine-5’-N-methyluronamide (A 3 agonist) affected P-SMC proliferation or migration. 2-Chloroadenosine increased cyclic AMP, reduced Akt phosphorylation (activates cyclin D expression), and reduced levels of cyclin D1 (promotes cell-cycle progression). Moreover, 2-chloroadenosine inhibited expression of Skp2 (promotes proteolysis of p27 Kip1 ) and upregulated levels of p27 Kip1 (negative cell-cycle regulator). A 2B receptor knockdown prevented the effects of 2-chloroadenosine on cyclic AMP production and P-SMC proliferation and migration. Likewise, inhibition of adenylyl cyclase and protein kinase A rescued P-SMCs from the inhibitory effects of 2-chloroadenosine. The inhibitory effects of adenosine were similar in male and female P-SMCs. In vivo, peri-arterial (rat carotid artery) 2-chloroadenosine (20 μmol/L for 7 days) reduced neointimal hyperplasia by 64.5% ( P 2B receptor/cyclic AMP/protein kinase A axis, which reduces cyclin D1 expression and activity via inhibiting Akt phosphorylation and Skp2 expression and upregulating p27 kip1 levels. Adenosine attenuates neointima formation in part by inhibiting infiltration and proliferation of c-Kit+ P-SMCs. |
| Databáze: | OpenAIRE |
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