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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H77    most recent 01355.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in AJP - Heart 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 Google Scholar Google Scholar Articles by Gul, R. Articles by Kim, U.-H. Search for Related Content PubMed PubMed Citation Articles by Gul, R. Articles by Kim, U.-H.

A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes

¹Department of Biochemistry, ²Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Republic of Korea

Submitted 20 November 2007 ; accepted in final form 28 April 2008

ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca²⁺-mobilizing second messenger, cADP-ribose (cADPR), from NAD⁺. In this study, we investigated the molecular basis of ADPR-cyclase activation in the ANG II signaling pathway and cellular responses in adult rat cardiomyocytes. The results showed that ANG II generated biphasic intracellular Ca²⁺ concentration increases that include a rapid transient Ca²⁺ elevation via inositol trisphosphate (IP₃) receptor and sustained Ca²⁺ rise via the activation of L-type Ca²⁺ channel and opening of ryanodine receptor. ANG II-induced sustained Ca²⁺ rise was blocked by a cADPR antagonistic analog, 8-bromo-cADPR, indicating that sustained Ca²⁺ rise is mediated by cADPR. Supporting the notion, ADPR-cyclase activity and cADPR production by ANG II were increased in a time-dependent manner. Application of pharmacological inhibitors and immunological analyses revealed that cADPR formation was activated by sequential activation of Src, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), phospholipase C (PLC)-1, and IP₃-mediated Ca²⁺ signal. Inhibitors of these signaling molecules not only completely abolished the ANG II-induced Ca²⁺ signals but also inhibited cADPR formation. Application of the cADPR antagonist and inhibitors of upstream signaling molecules of ADPR-cyclase inhibited ANG II-stimulated hypertrophic responses, which include nuclear translocation of Ca²⁺/calcineurin-dependent nuclear factor of activated T cells 3, protein expression of transforming growth factor-β1, and incorporation of [³H]leucine in cardiomyocytes. Taken together, these findings suggest that activation of ADPR-cyclase by ANG II entails a novel signaling pathway involving sequential activation of Src, PI 3-kinase/Akt, and PLC-1/IP₃ and that the activation of ADPR-cyclase can lead to cardiac hypertrophy.

angiotensin II; calcium ion, adenosine 5'-triphosphate-ribosyl cyclase; cardiomyocytes

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Corrigendum

AJP - Heart 2008 295: H2220. [Full Text]  

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