p38 MAPK in cardioprotection - are we there yet?

Br J Pharmacol. 2015 Apr;172(8):2101-13. doi: 10.1111/bph.12901. Epub 2014 Nov 24.

Abstract

PKs transfer a phosphate from ATP to the side-chain hydroxyl group of a serine, threonine or tyrosine residue of a substrate protein. This in turn can alter that protein's function; modulating fundamental cellular processes including, metabolism, transcription, growth, division, differentiation, motility and survival. PKs are subdivided into families based on homology. One such group are the stress-activated kinases, which as the name suggests, are activated in response to cellular stresses such as toxins, cytokines, mechanical deformation and osmotic stress. Members include the p38 MAPK family, which is composed of α, β, γ and δ, isoforms which are encoded by separate genes. These kinases transduce extracellular signals and coordinate the cellular responses needed for adaptation and survival. However, in cardiovascular and other disease states, these same systems can trigger maladaptive responses that aggravate, rather than alleviate, the disease. This situation is analogous to adrenergic, angiotensin and aldosterone signalling in heart failure, where inhibition is beneficial despite the importance of these hormones to homeostasis. The question is whether similar benefits could accrue from p38 inhibition? In this review, we will discuss the structure and function of p38, the history of p38 inhibitors and their use in preclinical studies. Finally, we will summarize the results of recent cardiovascular clinical trials with p38 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / therapeutic use
  • Humans
  • Myocardium / metabolism
  • Protein Conformation
  • Protein Isoforms
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cardiotonic Agents
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • p38 Mitogen-Activated Protein Kinases