P38 MAPK Pathway in the Heart: New Insights in Health and Disease.

Rafael Romero-Becerra,Cintia Folgueira,Guadalupe Sabio,Ayelén Santamans

doi:10.3390/ijms21197412

Rafael Romero-Becerra, Cintia Folgueira + Show 2 more

Open Access

https://doi.org/10.3390/ijms21197412

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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.

Highlights

Introduction p38α was identified by three groups in 1994 as a 38 kDa polypeptide that was phosphorylated after exposure to lipopolysaccharide (LPS), hyperosmolarity, or interleukin 1 (IL-1), that directly phosphorylates and activates the upstream kinase MAPKAP-K2 [1,2,3]
P38 activity is regulated by phosphorylation at the end of a cascade composed of a MAPK kinase (MKK) and an MKK kinase (MEKK) [11,12,13]
The p38s are activated by MKK-mediated dual phosphorylation of tyrosine and threonine residues in the conserved Thr–Xaa–Tyr motif [14]

Summary

Introduction

P38α was identified by three groups in 1994 as a 38 kDa polypeptide that was phosphorylated after exposure to lipopolysaccharide (LPS), hyperosmolarity, or interleukin 1 (IL-1), that directly phosphorylates and activates the upstream kinase MAPKAP-K2 [1,2,3]. The p38 family members are encoded by different genes, located tandemly in two chromosomes. The p38 family can be subdivided into two subsets, with p38α and p38β in one group and p38γ and p38δ in the other This classification is based partly on amino-acid sequence identity; p38α and p38β are 75% identical, whereas p38γ and p38δ are 62% and 61% identical to p38α, respectively, while sharing 70% sequence identity with each other. The cascade is initiated by one of several MKK-phosphorylating MAP3Ks in cell-type- and stimulus-dependent manner. These MAP3Ks include mixed-lineage kinases (MLK), TGF β-activated kinase 1 (TAK1), MAPK/ERK kinase kinases (MEKK), TAO1 and TAO2, and apoptosis signal-regulating kinase-1 (ASK1) [14]. We summarize current knowledge of p38 function in the heart and discuss recent advances

Cardiovascular Development

Cardiac Hypertrophy

Findings

Cardiac Regeneration