Activation of the Mineralocorticoid Receptor Increases Striatin Levels

Aldosterone (ALDO) is regulated by sodium intake and has direct adverse effects on the vasculature.1 Administration of mineralocorticoids leads to heart lesions.2 Impaired left ventricular diastolic function and prolonged PQ intervals are observed in patients with primary hyperaldosteronism.3,4 In addition, circulating ALDO levels correlate with cardiac damage5 and clinical studies with mineralocorticoid receptor (MR) antagonists show decreased morbidity and mortality in patients with heart failure.6 Consistent with these observations, animal studies demonstrated that mineralocorticoid excess may lead to myocardial inflammation and fibrosis.7,8 In vitro studies demonstrate direct effects of ALDO on plasminogen activator inhibitor-1 expression in cardiac cells9 and cardiac fibrosis and heart failure have been observed in a transgenic mouse model overexpressing 11β-hydroxysteroid dehydrogenase type 2 in cardiomyocytes.10 Moreover, MR interacts specifically with the cardiac myosin binding protein, suggesting a role of MR in cardiac remodeling.11 Increased ALDO levels lead to numerous signaling events.12 ALDO’s classical epithelial effect is to increase the transport of sodium via the effects of MR as a ligand-dependent transcription factor. These effects of ALDO are mediated in part by vesicular trafficking to the plasma membrane of proteins such as vacuolar H+-ATPase, Na+/H+ exchange isoform 3 and the epithelial sodium channel.13,14 There is evidence that ALDO mediates epithelial sodium channel trafficking to lipid rafts in the plasma membrane of A6 cells. However the mechanisms by which ALDO alters vascular tissue are not clear. Striatin is abundant in neurons where it is proposed to function as a scaffolding protein that interacts with mediators of vesicular trafficking.15–17 Striatin contains several protein association domains: a caveolin (cav)-binding motif, a coiled-coil structure, a Ca2+-calmodulin-binding site and a large WD-repeat domain.15,18 There is evidence that striatin’s WD-repeat domain interacts with GαI protein and Protein Phosphatase 2A (PP2A) allowing for rapid activation of several transduction molecules (e.g., endothelial nitric oxide synthase) and mitogen-activated protein kinase 19 More recently, striatin has been shown to be a key intermediary of the effects of estrogen receptor-α (ERα) activation.20 Lu et al. provided evidence that striatin’s N-terminal segment interacts with the DNA binding domain of ERα in the immortalized human endothelial cell line (EA.hy926) cells. This interaction organizes ERα-endothelial nitric oxide synthase membrane signaling leading to rapid nongenomic activation of endothelial nitric oxide synthase in EA.hy926 cells. Thus, the association between ERα and striatin raise the possibility that striatin may also interact with the MR. We determined the effects of salt restriction on striatin levels in vascular tissue. We studied the in vivo effects of dietary sodium restriction in mice and observed marked increases in the levels of striatin in the heart. Our results also show that vascular tissue express striatin and that striatin co-precipitates with MR. We then studied the direct effects of ALDO on striatin levels in human and mouse endothelial cells and tested the in vivo relevance of our findings in two mouse models of MR activation. Our results suggest that MR interacts with striatin and are consistent with a direct effect of ALDO on striatin levels in vivo.