Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale

Abstract

Among the myriad of intracellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart.

FIG. 1

Canonical mitogen-activated protein kinase (MAPK) signaling. MAPK are prototypically activated by canonical three-tiered sequential phosphorylation events. The most well-known MAPKKK and MAPKK are listed for each MAPK; however, this is only a small representation of all identified upstream kinases. Furthermore, multiple steps may exist between the cell stimulus and activation of the MAPKKK and between activation of the MAPK and the biological response.

FIG. 2

Representative MAPK signaling in the heart. MAPK signaling events that play a role in cardiac signaling. Not all connections necessarily represent a direct interaction but rather may represent the end product of multiple steps. These are only a general representation of a sample of signaling events in the heart and do not represent all known MAPK signaling. A: ERK signaling. B: JNK signaling. C: p38 signaling. D: ERK5 signaling.

FIG. 3

MAPK signaling during heart development. Proposed MAPK signaling events during various stages of heart development. FHF, first heart field; SHF, second heart field; CNC, cardiac neural crest; V, ventricle; A, atria; RA, right atrium; LA, left atrium; CT, conotruncus; RV, right ventricle; LV, left ventricle; AVV, atrioventricular valves; Ao, aorta; PA, pulmonary artery; DA, ductus arteriosus. [Modified from Srivastava (379).]