Mitogen-Activated Protein Kinases as Biomarkers of Hypertension or Cardiac Pressure Overload

Abstract

In hypertension, left ventricular hypertrophy is initially a useful compensatory process that represents an adaptation to increased ventricular wall stress. It is also one of the first steps toward overt clinical disease. Several changes in myocardial structure characterize hypertensive or pressure-overload heart disease that induces myocardial remodeling (eg, enhanced cardiomyocyte growth, excessive cardiomyocyte necrosis/apoptosis, accumulation of interstitial and perivascular collagen fibers, or disruption of the endomysial and perimysial collagen network).1 In the long term, these cellular changes, if untreated, will deteriorate left ventricular function and facilitate the development of heart failure. The growth and survival of adult cardiomyocytes, smooth muscle cells, and macrophages are regulated by extracellular ligands, growth factors, and cytokines that bind to cell-surface receptors and activate intracellular signal transduction cascades. These signaling pathways control essential processes in all eukaryotic cells, including gene transcription, protein translation, cytoskeletal remodeling, endocytosis, cell metabolism, cell proliferation, and survival.2 One of the best-described signal transmission systems activated by pressure overload involves multiple cascades of protein phosphorylation by the mitogen activated protein kinase (MAPK) family, with diverse roles in a broad range of physiological functions.3 The MAPK signaling pathway sequences ultimately result in the dual phosphorylation and activation of terminal kinases, such as p38, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERK1/2 and ERK5), which are involved in different cellular responses, including pressure-overload–induced cardiac hypertrophy.4 MAPK cascades are triple-kinase pathways that include an MAPK kinase kinase, an MAPK kinase, and a terminal MAPK. MAPK cascades may be …