Signal transduction and activator of transcription (STAT) protein-dependent activation of angiotensinogen promoter: a cellular signal for hypertrophy in cardiac muscle.

The role of the peptide hormone angiotensin (AngII) in promoting myocardial hypertrophy is well documented. Our studies demonstrate that AngII uses a signaling pathway in cardiac myocytes in which the promoter of the gene encoding its prohormone, angiotensinogen, serves as the target site for activated signal transduction and activator of transcription (STAT) proteins. Gel mobility-shift assay revealed that STAT3 and STAT6 are selectively activated by AngII treatment of cardiomyocytes in culture and bind to a sequence motif (St-domain) in the angiotensinogen promoter to activate its transcription in transient transfection assay. We have also observed a dramatic increase in the St-domain binding activity of STAT proteins in the hypertrophied heart of the genetically hypertensive rat relative to that of the aged-matched normotensive strain WKY, providing a compelling argument in favor of the linkage of STAT pathway to the heart tissue autocrine AngII loop. These studies thus uncover a mechanism by which the activation of a selective set of STATs underlies mobilization of the gene activation program intrinsic to cardiac hypertrophy.