Heart failure is a major health problem in the elderly. Evidence indicates that a cardiac aldosterone signaling system plays an important role in the fibrosis associated with heart failure. Spironolactone, an aldosterone receptor antagonist, counteracts some of the effects of aldosterone in culture and in vivo. Aldosterone exerts its effects in target cells by binding to the mineralocorticoid receptor (MR) and stimulating transcription of effector genes. According to this paradigm, increases in fibrosis can be explained by the action of the aldosterone-MR complex on cardiac fibroblast genes that encode extracellular matrix proteins. A number of observations are not explained by this paradigm, however, including our preliminary data suggesting that spironolactone treatment of old rats does not decrease fibrosis as predicted, but increases the collagen content of the heart. Another paradoxical finding is that conditonal suppression of MR expression in cardiac myocytes of transgenic mice leads to fibrosis and heart failure. Emerging evidence strongly suggests that rapid non-genomic effects of aldosterone may explain some of the confusion, but the mechanisms by which these non-genomic effects are enacted have been elusive.
The specific aims of this proposal are to identify novel protein mediators of aldosterone action that may regulate the age-associated increases in fibrosis and to identify novel proteins that interact with aldosterone and/or the MR to account for the non-genomic effects of aldosterone. We will study existing heart tissue samples from young and old rats treated chronically with vehicle or spironolactone. We will also generate cardiac myocyte and cardiac fibroblast cell populations from isolated hearts of old rats perfused briefly with vehicle or aldosterone. Proteins from cytosolic and particulate fractions of each cell type will be prepared for proteomic analyses. 2-D gel electrophoresis will be employed to identify differentially expressed or posttranslationally modified proteins. We will target proteins involved in the aldosterone signaling system by immunoprecipitation of MR-associated proteins. These studies are expected to identify novel proteins that may mediate the effects of aldosterone in the aged failing heart. Identification of proteins involved in aldosterone signaling will lead to the development of new hypotheses for future grant proposals addressing their roles in the development of heart failure in the elderly.
| Hwang, Hyun Seok; Cirrincione, Georgina; Thomas, D Paul et al. (2007) Aldosterone antagonism fails to attenuate age-associated left ventricular fibrosis. J Gerontol A Biol Sci Med Sci 62:382-8 |
| Boluyt, Marvin O; Brevick, Julie L; Rogers, David S et al. (2006) Changes in the rat heart proteome induced by exercise training: Increased abundance of heat shock protein hsp20. Proteomics 6:3154-69 |
