p38 MAPK Pathway in the Heart: New Insights in Health and Disease

Abstract

The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. p38 function has been studied in depth in relation to cardiac development and function. The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action in part dependent on the model system under study and the identity of the activated p38 family member. Most studies to date have been performed with inhibitors that are not isoform-specific, and, consequently, knowledge remains very limited about how the different p38s control cardiac physiology and respond to cardiac stress. In this review, we summarize the current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field.

Keywords: MAPK; arrhythmia; hypoxia; metabolism; p38; physiology; signaling.

Figure 1

p38 in cardiovascular regeneration. (A) p38α blocks cardiovascular regeneration by inhibiting the expression of genes involved in cardiomyocyte proliferation and regeneration, such as Ect2, Crp1, ki67, cdc2, cyclin A, and p27, and reducing Rb phosphorylation to block cell-cycle progression. FGF1 stimulation has the opposite effect. (B) p38γ activates differentiation and myogenesis in satellite cells by phosphorylating MyoD and activating proliferation. p38α prevents p38γ activation in satellite cells, blocking regeneration. ↑ increase, ↓ decrease.

Figure 2

Dual role of p38 activation during preconditioning and ischemia–reperfusion injury. Activation of p38β during preconditioning triggers pro-survival signaling pathways, whereas decreased p38α activation during the ischemic episode leads to cardioprotection. On the other hand, ROS-induced p38α activation during the ischemic insult triggers HIF1-α stabilization; increases (↑) fibrosis, arrhythmias, and inflammation; and disrupts mitochondrial homeostasis. SB203580 administration during preconditioning increases myocardial injury, whereas administration during ischemia–reperfusion improves cardiac outcome. Indirect p38 downregulators, such as gamboge, statins, and antioxidants, seem to have beneficial effects when administered during or after the ischemia. Further research is needed to determine the precise reciprocity of ROS–p38 regulation. ↑ increase.

Figure 3

p38 in heart failure and cardiac arrhythmia. p38 activation participates in the development of heart failure and cardiac arrhythmia through three main mechanisms: (A) Increased cardiac fibrosis by induction of TNF-α and IL-6 in cardiomyocytes, differentiation of fibroblasts, and induction of TGF-β in cardiac myofibroblasts; (B) Reduced cardiac contractility due to dephosphorylation of a-tropomyosin and troponin I via PP2C-α/PP2C-β; (C) Promotion of cardiac arrhythmias due to reduced expression and activity of SERCA2 (Atp2a2), increased expression of NCX1 (Ncx1) and Cx43 (Cnx43), and altered Cx43 phosphorylation, inducing cardiac contractile dysfunction and altered action potential propagation. ↑ increase, ↓ decrease.