Mitogen-activated protein kinases in heart development and diseases

Abstract

Mitogen-activated protein (MAP) kinases belong to a highly conserved family of Ser-Thr protein kinases in the human kinome and have diverse roles in broad physiological functions. The 4 best-characterized MAP kinase pathways, ERK1/2, JNK, p38, and ERK5, have been implicated in different aspects of cardiac regulation, from development to pathological remodeling. Recent advancements in the development of kinase-specific inhibitors and genetically engineered animal models have revealed significant new insights about MAP kinase pathways in the heart. However, this explosive body of new information also has yielded many controversies about the functional role of specific MAP kinases as either detrimental promoters or critical protectors of the heart during cardiac pathological processes. These uncertainties have raised questions on whether/how MAP kinases can be targeted to develop effective therapies against heart diseases. In this review, recent studies examining the role of MAP kinase subfamilies in cardiac development, hypertrophy, and survival are summarized.

Figure 1

MAP kinases and their downstream effects in the heart. RTK indicates tyrosine kinase receptor; GPCR, G-protein–coupled receptor; ROS, reactive oxygen species; MEKK, MAP kinase, kinase, kinase; MLK, mixed-lineage kinase; ASK-1, apoptosis signal-regulating kinase; TAK, TGF-β–activated kinase; MEK or MKK, MAP kinase, kinase; SERCA, sarco/endoplasmic reticulum Ca(2+) ATPase; PLB, phospholamban; NCX, sodium-calcium exchanger: RyR, ryanodine receptor; DHPR, dihydropyrodine receptor; NFAT, nuclear factor of activated T-cells; GATA, GATA binding transcription factor; MEF, myocyte-specific enhancer-binding nuclear factor; HSP, heat shock proteins; mPTP, mitochondria permeability transition pore; ΔΨ, mitochondria inner membrane potential; PDE3A, phosphodiesterase 3A; and ICER, inducible cAMP early repressor.