Mitogen-Activated Protein Kinases in Heart Development and Diseases

Abstract

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.

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

“…The activation of both ERK and JNK pathways are thought to protect cardiomyocytes from apoptosis, although the role of p38 remains unclear. 28 We observed a lower expression of phosphorylated JNK and p38 in vehicle-treated SNX; this was prevented by R-568. One can speculate that normalization of JNK and p38 activation combined with the activation of ERK by the CaSR cause cardioprotection in this model.…”

“…26,27 Mitogen-activated protein kinase (MAPK) activity plays an important role in heart hypertrophy. 28 Holstein 29 showed that activation of the CaSR activates ERK-1/2 kinases. The ERK-1/2 signaling was shown to promote adaptive hypertrophy with normalized wall stress and compensation for increased load.…”

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

“…The p38 MAPK contains four family members, p38α, p38β, p38γ, and p38δ, and all share a conserved Thr-Gly-Tyr (TGY) dual-phosphorylation motif in the activation loop that can be phosphorylated by upstream MAPK kinases (MAPKK). Activation of p38 MAPK is thought to be mediated by a cascade of phosphorylation events involving upstream MAPKK, such as MKK3 and/or MKK6, as well as further upstream MAPKK kinases, such as TAK1 and ASK1 (21,22). This mechanism, by far, is the most widely studied and recognized canonical means to phosphorylate and activate p38 MAPK.…”

The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue

“…However, the molecular mechanisms and cellular signal transduction processes that underlie these cellular regulatory systems are still under intense investigation [9]. In this issue, this area of research is reviewed by contributions from the groups of Campbell Cardiac muscle cells are dynamic; increased mechanical load induces a hypertrophic response, while reduced load elicits the reverse response [21]. The cellular signal transduction processes responsible for this tight, long term, regulatory system that leads to remodeling of the sarcomeric architecture in the cardiac muscle cell are varied and complex.…”

“…Cardiac muscle cells are dynamic; increased mechanical load induces a hypertrophic response, while reduced load elicits the reverse response [21]. The cellular signal transduction processes responsible for this tight, long term, regulatory system that leads to remodeling of the sarcomeric architecture in the cardiac muscle cell are varied and complex.…”