A new tale of p21 activated protein kinase in the heart: Pathophysiology to drug discovery
Wang SB., Tsui H., Liu W., Lei M., Wang X.
Cardiovascular disease is the number one cause for morbidity and mortality worldwide. Possibilities for new therapies in the emerging field of cardiac signalling prompted extensive research on myocardial remodelling over the past decades. In this review, we assemble an overview of the recent findings on the multifunctional enzyme, p21-activated kinase 1 (Pak1), a member of a serine/threonine protein kinase family in the heart, particularly its cardiac protective effects. We present a model for Pak1 signaling that provides a mechanism for specifically affecting cardiac cellular processes. We discuss its cardiac protective effects such as anti-hypertrophy, anti-ischaemic injury and role in maintaining ventricular Ca 2+ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions. We also discuss the potentials of Pak1 activation by naturally occurring sphingosine and its analogues FTY720, and bioactive peptides designed to diminish Pak1 auto-inhibition as novel therapeutics for major cardiovascular diseases.