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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1918    most recent 00416.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Merla, R. Articles by Birnbaum, Y. Search for Related Content PubMed PubMed Citation Articles by Merla, R. Articles by Birnbaum, Y.

The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation

¹Department of Internal Medicine and ²Division of Cardiology and ³Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Submitted 4 April 2007 ; accepted in final form 5 July 2007

Statins activate phosphatidylinositol-3-kinase, which activates ecto-5'-nucleotidase and phosphorylates 3-phosphoinositide-dependent kinase-1 (PDK-1). Phosphorylated (P-)PDK-1 phosphorylates Akt, which phosphorylates endothelial nitric oxide synthase (eNOS). We asked if the blockade of adenosine receptors (A₁, A_2A, A_2B, or A₃ receptors) could attenuate the induction of Akt and eNOS by atorvastatin (ATV) and whether ERK1/2 is involved in the ATV regulation of Akt and eNOS. In protocol 1, mice received intraperitoneal ATV, theophylline (TH), ATV + TH, or vehicle. In protocol 2, mice received intraperitoneal injections of ATV, U0126 (an ERK1/2 inhibitor), ATV + U0126, or vehicle; 8 h later, hearts were assessed by immunoblot analysis. In protocol 3, mice received intraperitoneal ATV alone or with 8-sulfophenyltheophylline (SPT); 1, 3, and 6 h after injection, hearts were assessed by immunoblot analysis. In protocol 4, mice received intraperitoneal ATV alone or with SPT, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), alloxazine, or MRS-1523; 3 h after injection, hearts were assessed by immunoblot analysis. ATV increased P-ERK, P-PDK-1, Ser⁴⁷³ P-Akt, Thr³⁰⁸ P-Akt, and P-eNOS levels. TH blocked ATV-induced increases in P-ERK, Ser⁴⁷³ P-Akt, Thr³⁰⁸ P-Akt, and P-eNOS levels without affecting the induction of P-PDK-1 by ATV. U0126 blocked the ATV induction of Ser⁴⁷³ P-Akt and Thr³⁰⁸ P-Akt while attenuating the induction of P-eNOS. A detectable increase in P-ERK, Ser⁴⁷³ P-Akt and P-eNOS was seen 3 and 6 h after injection but not at 1 h. DPCPX, CSC, and alloxazine partially blocked the ATV induction of P-ERK, Ser⁴⁷³ P-Akt, and P-eNOS. In conclusion, blockade of adenosine A₁, A_2A, and A_2B receptors but not A₃ receptors inhibited the induction of Akt and eNOS by statins. Adenosine was required for ERK1/2 activation by statins, which resulted in Akt and eNOS phosphorylation.

extracellular signal-regulated kinase 1/2; endothelial nitric oxide synthase

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