Different activation of MAPKs and Akt/GSK3β after preload vs. afterload elevation

Abstract

Aims Pressure overload (PO) and volume overload (VO) lead to concentric or eccentric hypertrophy. Previously, we could show that activation of signalling cascades differ in in vivo mouse models. Activation of these signal cascades could either be induced by intrinsic load sensing or neuro‐endocrine substances like catecholamines or the renin‐angiotensin‐aldosterone system. Methods and results We therefore analysed the activation of classical cardiac signal pathways [mitogen‐activated protein kinases (MAPKs) (ERK, p38, and JNK) and Akt‐GSK3β] in in vitro of mechanical overload (ejecting heart model, rabbit and human isolated muscle strips). Selective elevation of preload in vitro increased AKT and GSK3β phosphorylation after 15 min in isolated rabbit muscles strips (AKT 49%, GSK3β 26%, P < 0.05) and in mouse ejecting hearts (AKT 51%, GSK49%, P < 0.05), whereas phosphorylation of MAPKs was not influenced by increased preload. Selective elevation of afterload revealed an increase in ERK phosphorylation in the ejecting heart (43%, P < 0.05), but not in AKT, GSK3β, and the other MAPKs. Elevation of preload and afterload in the ejecting heart induced a significant phosphorylation of ERK (95%, P < 0.001) and showed a moderate increased AKT (P = 0.14) and GSK3β (P = 0.21) phosphorylation, which did not reach significance. Preload and afterload elevation in muscles strips from human failing hearts showed neither AKT nor ERK phosphorylation changes. Conclusions Our data show that preload activates the AKT–GSK3β and afterload the ERK pathway in vitro, indicating an intrinsic mechanism independent of endocrine signalling.

The Role of Extracellular Signal-Regulated Kinase Pathways in Different Models of Cardiac Hypertrophy in Rats

“…They showed that maladaptive cardiac hypertrophy in the afterload model was associated with apoptosis and fibrosis, whereas preload was associated with less apoptosis, better cardiac function, and no fibrosis [ 26 ]. Recently, Hartmann et al also reported the results of in vitro mechanical overload on ejection heart models in rabbit and human isolated muscle strips and found that selective afterload elevation results in ERK phosphorylation, whereas preload activates the AKT-GSK3β pathway, which plays a role in preventing cell apoptosis [ 27 , 28 ].…”