The p38 mitogen-activated protein kinase pathway—A potential target for intervention in infarction, hypertrophy, and heart failure

Abstract

The p38 mitogen-activated protein kinases (p38s) are stress activated ser/thr kinases. Their activation has been associated with various pathological stressors in the heart. Activated p38 is implicated in a wide spectrum of cardiac pathologies, including hypertrophy, myocardial infarction, as well as systolic and diastolic heart failure. In this review, the specific contribution of different isoforms of p38 kinases to cardiac diseases as well as TAB-1 mediated non-canonical activation pathway are discussed as a rationale for inhibiting p38 activity to treat cardiac hypertrophy, ischemic injury and heart failure. Finally, a summary of current clinical trials targeting p38 kinases in cardiovascular diseases is provided to highlight the potential promise as well as existing challenges of this therapeutic approach.The p38 mitogen-activated protein kinases (p38s) are stress-activated kinases that together with the extracellular signal-regulated kinases 1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinase 5 (ERK5) form the 4 principal limbs of the mitogen-activated protein kinase (MAPKs) system. The MAPKs are serine/threonine protein kinases that can be activated by ligands of G-protein-coupled, and growth factor, receptors, as well as other stressors such as reactive oxidative species. Isoforms of p38 and their mechanism of activationFour p38 isoforms (α, β, γ and δ) exist which have preserved structure but variable sensitivity to pharmacological inhibition. p38α and β have high sequence homology and share sensitivity to pharmacological inhibition by pyridinyl imidazole molecules (such as SB203580) but have only 60% homology with p38γ and δ which are resistant to inhibition by SB203580 [1].

Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling

“…32,33 Inhibiting p38 and JNK1/2 signaling with an appropriate pharmacological agent could delay the transition toward heart failure. 20,34 These results suggest that the heart-protective role of USP18 is likely attributed to its interference with p38 and JNK1/2 signaling.…”

Tripartite Motif 8 Contributes to Pathological Cardiac Hypertrophy Through Enhancing Transforming Growth Factor β–Activated Kinase 1–Dependent Signaling Pathways

“…Given that mitogen-activated protein kinase signaling pathways, including ERK1/2, p38, and JNK1/2, have been shown to play important roles in cardiac hypertrophy, [24][25][26] Western blots were performed to analyze whether TRIM8 regulates mitogen-activated protein kinase signaling pathways. Our study demonstrated that the exaggerated hypertrophic response in TRIM8-transgenic hearts was accompanied by enhanced activation of P38 and JNK1/2.…”

“…These factors are well-accepted critical players in the development of pathological cardiac hypertrophy and HF. [24][25][26] In response to pressure overload, neither the absence nor the overexpression of TRIM8 in mouse hearts altered the activity of MEK1/2 and ERK1/2. Conversely, the AB-induced activation of P38 and JNK1/2 was significantly attenuated in TRIM8-knockout hearts but enhanced in TRIM8-transgenic hearts ( Figure 5A and 5B).…”

Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

“…All of these pathways have also been shown to be activated in the myocardium early after experimental MI; see recent comprehensive reviews on NF-κB (Gordon et al, 2011), p38 (Marber et al, 2011;Turner, 2011), JNK (Turner, 2011), ERK and Akt; the latter being components of the reperfusion injury salvage kinase (RISK) pathway that is considered cardioprotective (Hausenloy et al, 2005). However, these studies do not shed particular light on IL-1 signalling in CF due to the heterogeneity of cell types in the 16 heart and the multitude of potential stimuli for these pathways after MI (in addition to IL-1).…”

“…The p38 MAPK pathway plays an important role in regulating various aspects of the myocardial remodelling process, including CF function (Marber et al, 2011;Turner, 2011).…”