PI3K and MAPK Activation During Eccentric Cardiac Hypertrophy

Abstract

Development of cardiac hypertrophy is partly mediated by humoral factors such as IGF‐1. The role of related kinases in the development of cardiac hypertrophy is still unclear. This study elucidates the role of MAPK and PI‐3K in the transduction of IGF‐I signaling during the development of eccentric cardiac hypertrophy. Adult Sprague‐Dawley rats were shunted (aorto‐caval) to induce eccentric cardiac hypertrophy which developed over 2 weeks. Hearts were retrogradely superfused with Tyrode (control), or IGF‐I (10−8M) or respective kinase inhibitor (10−6M) in the presence or absence of IGF‐I (10−8M). MRI showed an increase in LV‐EDV (62%) and its wall thickness (40%) in the shunt rat, concurrent with greater relative heart weight. Hypertrophied hearts had higher activity levels for ERK1/ERK2 (54%/157%), p38 (57%) and Akt (64%) as measured by western blot. In normal hearts, IGF‐I increased the activity of ERK1/ERK2 (38%/105%), p38 (109%) and Akt (95%); whereas in the hypertrophied hearts it increased only that of Akt (2.4 fold). Treatment with either ERK1/2 inhibitor (PD98059; 10−6M), p38 inhibitor (SB203580, 10−6M) or PI‐3K inhibitor (LY294002, 10−6M) reduced the activation level of the respective kinase in the hypertrophied hearts only. LY294002 reduced the activation of Akt by IGF‐I in both sham (62%) and shunt (75%). Thus we conclude that IGF‐I effects are mediated by PI‐3K and not MAPK in the hypertrophied hearts.