Aldosterone-mediated endothelial remodeling and oxidative stress

The recognition of the inflammatory and profibrotic role of aldosterone in the pathophysiology of cardiovascular disease, via its effect on endothelial dysfunction, is of growing importance, as demonstrated by the results of the recently concluded Randomized Aldactone Evaluation Study (RALES)1, and the EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS)2. These studies have, in fact, indicated the reduction of aldosterone effects through receptor blocking as additional benefit to patients with cardiovascular diseases. In a paper published in the May issue Kidney International, Oberleithner documented “in vitro” an aldosterone remodeling effect on human endothelium through induction of cell stiffness due to a presumably aldosterone induced oxidative stress via modulation of NAD(P)H oxidase3. We would like to provide further support to the contention of a specific remodeling and profibrotic action of aldosterone with the demonstration “ex vivo” in human mononuclear cells, recently published by our laboratory4, that indicates that aldosterone has a direct effect on oxidative stress through its ability to increase the levels of p22phox, an important subunit of NADPH oxidase, essential for superoxide anion generation. It, in fact, functions as an integral subunit of the final electron transport from NADPH to heme and molecular oxygen in generating superoxide anions. The aldosterone-induced increased level of PAI-1, a recognized profibrotic protein, we have shown in the same study4, may also provide a direct link to the cardiovascular profibrotic and remodeling action of aldosterone. Our findings were further strengthened by similar effects shown by glycyrrhetinic acid4, a constituent of licorice root, which is known to have a direct mineralocorticoid-like effect5. Thus, the report of Oberleithner3 in combination with the results of our study provides clear evidence for the aldosterone-related vascular remodeling effects through its induction of oxidative stress and oxidative stress-related profibrotic molecules, such as PAI-1.