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

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. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.”

Research Highlights
► p38 MAP kinases are activated in stressed myocardium.
► p38α and β isoforms have specific and differential roles in cardiac physiology and pathology.
► p38 kinase can be activated by different pathological stressors via upstream kinases or TAB-1 mediated non-canonical pathway.
► Specific inhibition of p38 based on different activation mechanisms is a potential therapeutic venue for heart diseases.