Ca2+-dependent signaling pathways through calcineurin and Ca2+/calmodulin-dependent protein kinase in development of cardiac hypertrophy

Cardiac hypertrophy is induced by a variety of cardiovascular diseases such as hypertension, valvular diseases, myocardial infarction, cardiomyopathy, and endocrine disorders. Although cardiac hypertrophy may be initially a beneficial response that normalizes wall stress and maintains normal cardiac function, prolonged hypertrophy becomes a leading cause of heart failure and sudden death. A number of studies have elucidated molecules responsible to the development of cardiac hypertrophy, including protein kinase C (PKC), protein kinase A (PKA), Raf-1 kinase, mitogen-activated protein (MAP) kinase fan-lily, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) family, Ras, and Rho family. It has been reported that Ca2+ regulates a number of cellular processes including cardiac hypertrophy. Since most hypertrophic signaling pathways are associated with an increase in intracellular Ca2+, Ca2+-dependent signaling pathways may be critical targets for therapies designed to prevent the progression of cardiac hypertrophy. Recently, a Ca2+/calmodulin-dependent protein kinase, and a Ca2+/calmodulin-dependent protein phosphatase, calcineurin, have attracted much attention as critical molecules that induce cardiac hypertrophy. In this review, we summarize the Ca2+-dependent signaling pathways through Ca2+/Calmodulindependent protein kinase and calcineurin in cardiac hypertrophy.