Contribution of PI 3-kinase isoforms to angiotensin II- and α-adrenoceptor-mediated signalling pathways in cardiomyocytes

Sibylle Wenzel, Justus-Liebig-Universität, Germany
Yaser Abdallah, Aga Khan University
Simone Helmig, Justus-Liebig-Universität, Germany
Claudia Schäfer, Justus-Liebig-Universität, Germany
Hans Michael Piper, Justus-Liebig-Universität, Germany
Klaus Dieter Schlüter, Justus-Liebig-Universität, Germany

This work was published before the author joined Aga Khan University.



Angiotensin II stimulation increases the formation of reactive oxygen species (ROS), the phosphorylation of p38 mitogen-activated protein kinase (MAPK), and the expression of transforming growth factor beta (TGFβ) in adult cardiomyocytes. The aim of this study was to determine the involvement of PI 3-kinase and to specify the participation of different isoforms in the angiotensin II-induced formation of ROS in comparison to the hypertrophic pathway triggered by α-adrenoceptor stimulation.


Freshly isolated myocytes were used to examine formation of ROS via H2DCF fluorescence. p38 MAPK phosphorylation, p70S6-kinase phosphorylation, PI 3-kinase, and TGFβ expression were measured by Western blotting. Sense and antisense oligonucleotides were used to down-regulate diverse PI 3-kinase isoforms. Hypertrophy was measured by 14C-phenylalanine incorporation and cell volume.


Inhibition of PI 3-kinase by Ly294002 or wortmannin, two inhibitors, decreased formation of ROS, phosphorylation of p38 MAPK, and TGFβ expression. Down-regulation of the p110β isoform by antisense oligonucleotides inhibited the angiotensin II-induced signalling pathway but not the α-adrenoceptor-mediated hypertrophic growth of cardiomyocytes. In contrast, down-regulation of the p110α isoform decreased the α-adrenoceptor-mediated hypertrophic growth of cardiomyocytes but did not affect the angiotensin II-mediated signalling pathway.


Thus, our study identifies an involvement of PI 3-kinase in the angiotensin II-induced formation of ROS and provides a biochemical basis for ligand-specific responses for angiotensin II and α-adrenoceptor stimulation as relates to hypertrophy.