Downregulation of Ca2+ signalling proteins in cardiac hypertrophy.

Calcium (Ca2+) signaling plays an essential role in several functions of cardiac myocytes. Transient rises and reductions of cytosolic Ca2+, permitted by the sarcoplasmic reticulum Ca2+ ATPase and other proteins, control each cycle of contraction and relaxation. Prolonged rises of cytosolic Ca2+ are involved in transcriptional activation, including the hypertrophy program. Furthermore, activation of transcriptional pathways produced by excitation of membrane receptors and involving Protein Kinases C and D, calcineurin, mitogen-activated protein kinases and glycogen synthase kinase 3b, generate competitive recruitment of transcriptional factors whereby Ca2+ signaling proteins are downregulated in cardiac hypertrophy. This imbalance leads to defects of muscle contraction (i.e., systole) and relaxation (i.e., diastole), and ultimately cardiac failure. Extensive experimentation on gene transfer and gene deletion is under way to clarify the role of Ca2+ signaling proteins in cardiac hypertrophy and failure, and to evaluate the possibility of gene therapy. On the other hand, the need for pharmacological agents directed to function or transcription/expression of Ca2+ signaling proteins is emphasized, considering their easier delivery and wide population targeting.