Mitogen-Activated Protein Kinase Signaling in the Heart: Angels Versus Demons in a Heart-Breaking Tale

Abstract

Among the myriad of intra-cellular 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.

Network Reconstruction and Systems Analysis of Cardiac Myocyte Hypertrophy Signaling

“…Increased cell size was seen in neonatal rat cardiac myocytes with microinjection of an activated Ras mutant (34), overactivated JNK by constitutively active MKK7 (35), overactivated p38 by constitutively active MKK6 (33), and expression of constitutively active MEK1 (36). Although in vitro experiments show pro-hypertrophic effects for JNK, MEK1/2, and p38, in vivo experiments have generated more conflicting results (37). Additional studies are needed to conclusively show the relative contributions of these ligands to various cardiac hypertrophy phenotypes in myocytes.…”

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

“…Although numerous studies have revealed crucial proteins and pathways involved in the process of cardiac hypertrophy, including the mitogen‐activated protein kinase (MAPK)3 and phosphatidylinositol 3 kinase–AKT–mammalian target of rapamycin (mTOR)4, 5, 6 signaling pathways, the underlying mechanism of cardiac hypertrophy remains elusive. Recently, numerous studies have reported the effects of immunologic molecules in cardiac hypertrophy 7, 8, 9.…”

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

“…Like atRA, mitogen-activated protein kinases (MAPK) play an essential role in cell proliferation and differentiation [16][17][18][19][20]. These kinases are components of signaling cascades that relay extracellular stimuli to transcription factors in the nucleus.…”

“…ERK activity is required for adipogenesis [30][31][32][33], but its influence in myogenesis is uncertain. Indeed, ERK was either judged to be unnecessary or necessary to myogenic differentiation [20,23,24]. Overall, those studies relied on different cell differentiation protocols to induce adipogenesis and myogenesis, preventing the unambiguous determination of the extent to which ERK and p38 influence undifferentiated cells to become adipocytes or myocytes.…”

“…This aspect of retinoid status could explain some inconsistencies observed between in vitro and in vivo situations. For instance, while some studies have implicated p38 as an important player in cardiomyogenesis in cell cultures, various strategies of p38 knockout resulted in normal development of the heart [17,20]. In the same line of thought, it is worth of note that retinoid agonists had different effects on differentiation into visceral endoderm in cell cultures depending upon which RAR and RXR had been knockout [59].…”