A new look at phospholamban in pressure-overload hypertrophy

Abstract

THE QUESTION OF THE MECHANISMS of pathological cardiac hypertrophy and the relationship of changes in cellular function to a myriad of clinical symptoms has long been an important and intriguing puzzle to researchers. How is it that exercise induces signaling changes that are beneficial to heart function but pathological conditions such as hypertension or valvular disease are associated with a loss of hemodynamic function and neurohumoral response, although both produce muscular hypertrophy? What are the interactions between hypertrophic and contractile signaling pathways? One point of interest is the increase in sympathetic drive observed in the pressure-overloaded (PO) hypertrophic heart that is accompanied by decreased -adrenergic sensitivity and diminished contractile reserve. This condition is significant to patients in that it causes a loss of ability to tolerate exercise and can lead to myocyte death and heart failure, but the cellular changes underlying the loss of contractile reserve are not entirely clear. A number of researchers have identified mechanisms for this loss of contractile reserve, but this picture is not complete. One prominent mechanism involved in the loss of adrenergic response is a downregulation of -adrenergic receptor (-AR) density, which is improved by administration of -blockers (4). Another is upregulation of -receptor kinase 1 (or G proteincoupled receptor kinase 2, GRK2; see Ref. 1), which inactivates -ARs and is reversible by exercise training (2). In the current issue of the American Journal of PhysiologyHeart and Circulatory Physiology, Mills et al. (3) have addressed the question of what downstream mechanisms may be involved in the diminution of adrenergic contractile reserve using a feline model of PO-induced left ventricular hypertrophy. They propose that altered abundance or basal phosphorylation state of target regulatory proteins, specifically phospholamban (PLB), is a central cause of the loss of inotropic responsiveness in PO animals. They have presented compelling in vivo evidence that aortic banded animals have a blunted systolic function that is not restored with dobutamine, concurrent with reduced total PLB and a significant increase in total PLB phosphorylation that is mainly attributed to the calmodulin kinase II site, Thr 17 . They also report that the less the response to dobutamine, the greater the level of Thr 17 phos