Cardiovascular, Pulmonary and Renal Pathology MDM2: A Novel Mineralocorticoid-Responsive Gene Involved in Aldosterone-Induced Human Vascular Structural Remodeling

Aldosterone has been demonstrated to play an important role in the pathogenesis of various cardiovascular diseases. Vascular structural remodeling, including vascular smooth muscle cell (VSMC) proliferation, has been also reported in small resistance arteries of patients with primary aldosteronism. Therefore, in this study, we examined whether genes involved in the regulation of the cell cycle were induced by aldosterone alone in cultured human VSMCs and in human small resistance arteries. Results of these studies eventually demonstrated that MDM2 , one of the genes involved in anti-apoptosis and cell growth, was markedly increased in mineralocorticoid receptor (MR)-positive VSMCs by aldosterone in all microarray, reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence analyses. In addition, an analysis using small interfering RNA demonstrated that this gene product was involved in cell proliferation of VSMCs induced by aldosterone. Eplerenone, a specific MR antagonist, inhibited this gene induction by aldosterone in VSMCs. MDM2 protein was also more abundant in VSMCs of small resistance arteries in patients with primary aldosteronism compared with a control population. MDM2 is therefore considered one of the mineralocorticoid-responsive genes that regulates cell proliferation of VSMCs induced by MR-mediated aldosterone stimulation, possibly playing an important role in aldosteroneinduced vascular structural remodeling. (Am J Pathol 2006, 169:362–371; DOI: 10.2353/ajpath.2006.051351) Aldosterone is a steroid hormone synthesized in the zona glomerulosa of human adrenal cortex as a result of stimulation by angiotensin II and others. Aldosterone has been demonstrated to bind to the mineralocorticoid receptor (MR) and to increase systemic blood pressure by regulating systemic electrolytes and volume balance in kidney, subsequently resulting in various human cardiovascular diseases. However, aldosterone has also been demonstrated to directly exert its effects on cardiovascular systems via MR. For instance, aldosterone has been reported to induce expression of some genes involved in vascular fibrosis, calcification, and inflammation, which are all considered important in pathology of vascular injuries. Aldosterone also induce mitogenesis of vascular smooth muscle cells (VSMCs), resulting in vascular structural remodeling under the presence of angiotensin II. However, aldosterone itself without the presence of angiotensin II is also considered to cause cardiovascular injuries. Vascular structural remodeling in small resistance arteries has been reported in patients with primary aldosteronism, where serum aldosterone levels were elevated but serum angiotensin II level is markedly down-regulated. In addition, aldosterone itself has been also demonstrated to stimulate proliferation of VSMCs. Therefore, aldosterone may directly induce some MR-responsive gene associated with regulation of the cell cycle in VSMCs, although inflammatory reaction and fibrosis are also very important features for aldosterone-induced vascular injuries and alterations. Jaffe and Mendelsohn recently reported that some MR-mediated genes were associated with vascular injuries in VSMCs