| Autor: |
Kunduri, Swati S., Mustafa, S. Jamal, Ponnoth, Dovenia S., Dick, Gregory M., Nayeem, Mohammed A. |
| Zdroj: |
Journal of Cardiovascular Pharmacology; July 2013, Vol. 62 Issue: 1 p78-83, 6p |
| Abstrakt: |
Adenosine A1receptor (A1AR) activation contracts smooth muscle, although signaling mechanisms are not thoroughly understood. Activation of A1AR leads to metabolism of arachidonic acid, including the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504a (CYP4a). The 20-HETE can activate protein kinase C- (PKC-), which crosstalks with extracellular signal-regulated kinase (ERK12) pathway. Both these pathways can regulate smooth muscle contraction, we tested the hypothesis that A1AR contracts smooth muscle through a pathway involving CYP4a, PKC-, and ERK12. Experiments included isometric tension recordings of aortic contraction and Western blots of signaling molecules in wild type (WT) and A1AR knockout (A1KO) mice. Contraction to the A1-selective agonist 2-chloro-N cyclopentyladenosine (CCPA) was absent in A1KO mice aortae, indicating the contractile role of A1AR. Inhibition of CYP4a (HET0016) abolished 2-chloro-N cyclopentyladenosine–induced contraction in WT aortae, indicating a critical role for 20-HETE. Both WT and A1KO mice aortae contracted in response to exogenous 20-HETE. Inhibition of PKC- (Gö6976) or ERK12 (PD98059) attenuated 20-HETE–induced contraction equally, suggesting that ERK12 is downstream of PKC-. Contractions to exogenous 20-HETE were significantly less in A1KO mice; reduced protein levels of PKC-, p-ERK12, and total ERK12 supported this observation. Our data indicate that A1AR mediates smooth muscle contraction via CYP4a and a PKC-–ERK12 pathway. |
| Databáze: |
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