The case for inhibiting p38 mitogen-activated protein kinase in heart failure

Abstract

This minireview discusses the evidence that the inhibition of p38 mitogen-activated protein kinases (p38 MAPKs) maybe of therapeutic value in heart failure. Most previous experimental studies, as well as past and ongoing clinical trials, have focussed on the role of p38 MAPKs in myocardial infarction and acute coronary syndromes. There is now growing evidence that these kinases are activated within the myocardium of the failing human heart and in the heart and blood vessels of animal models of heart failure. Furthermore, from a philosophical viewpoint the chronic activation of the adaptive stress pathways that lead to the activation of p38 MAPKs in heart failure is analogous to the chronic activation of the sympathetic, renin-aldosterone-angiotensin and neprilysin systems. These have provided some of the most effective therapies for heart failure. This minireview questions whether similar and synergistic advantages would follow the inhibition of p38 MAPKs.

Keywords: MAPK; fibrosis; heart failure; hypertrophy; inflammation; p38.

Figure 1

The downstream effects of p38 in cardiomyocytes, fibroblasts, and vasculature during heart failure. (A) Emphasized in red are the effects of p38 which are associated with the progression of heart failure. p38 activity has been linked to increased interstitial fibrosis (Wang et al., ; Ma et al., 1999), reduced vasoreactivity (Behr et al., ; Vijayan et al., ; Kumar et al., ; Hoefer et al., 2010) and increased ROS production (Li et al., ; Aukrust et al., ; Denise Martin et al., ; Elkhawad et al., 2012). The effects on the force of cardiomyocyte contraction are mediated by the effect of p38 on the Ca²⁺ transient (Andrews et al., ; Kaikkonen et al., 2014) and the sensitivity of the sarcomeres (Liao et al., ; Kan et al., ; Vahebi et al., 2007). (B) Schematic showing balance between stresses on the heart that lead to healthy adaptation and the pathological increases in cytokines and neurohormones that lead to, or aggravate, heart failure. The question is whether these pathological signals can be reversed by inhibiting p38?