Abstract 9809: Upregulation of Aldosterone by Steroidogenesis Acute Regulatory Protein (StAR) is Associated With Connective Tissue Growth Factor-Mediated Pulmonary Vascular Fibrosis in Pulmonary Arterial Hypertension In Vivo
Hyperaldosteronsim is associated with increased pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH). In cardiomyocytes, aldosterone (ALDO) promotes collagen deposition by increasing levels of connective tissue growth factor (CTGF). The role of CTGF in ALDO-mediated vascular remodeling in PAH, however, is not known. We hypothesized that upregulation of CTGF by ALDO is a novel signaling mechanism that modulates pulmonary vascular fibrosis in PAH. To test this hypothesis, cultured human pulmonary artery endothelial cells were exposed to ALDO (10-9-10-7 mol/l) for 24 hr and changes in CTGF levels were assessed by immunoblotting. Compared to vehicle control, ALDO induced a dose-dependent increase in CTGF expression (3.4 ± 0.2 vs. 6.7 ± 1.9 vs. 10.4 ± 1.6 vs. 17.6 ± 1.9 units, P=0.02). We next investigated the effect of ALDO on CTGF in PAH in vivo. Compared to controls, rats exposed to SU-5416 (20 mg/kg) and hypoxia (10% O2) (Su/Hyp) for 21 d demonstrated increased pulmonary artery systolic pressure (PASP) (26 ± 2 vs. 81 ± 5 mmHg, P<0.05), which was associated with a 397% (P<0.02) increase in plasma ALDO levels. Next, we investigated changes in levels of steroidogenic acute regulatory protein (StAR) as a mechanism by which to account for hyperALDO in PAH. Compared to controls, immunohistochemistry revealed increased StAR in the pulmonary arterioles of Su/Hyp-PAH rats (19.2 ± 0.9 vs. 30.2 ± 0.5 units, P<0.01) and in patients with PAH (14.3 ± 1.4 vs. 19.3 ± 0.9 units, P<0.02). Immunohistochemistry revealed that compared to controls, Su/Hyp-PAH rats expressed increased levels of CTGF (88.1 ± 11.5 vs. 171.8 ± 5.9 units, P<0.01) and collagen III (61.5 ± 18.7 vs. 126.5 ± 6.3 units, P<0.01) in pulmonary arterioles. ALDO antagonism with eplerenone (0.6 mg/g chow) decreased CTGF and collagen III levels in SU/Hyp-PAH by 81% (p<0.01) and 38% (P<0.01), respectively, to decrease PASP (81 ± 5 vs. 62 ± 7 mmHg, P<0.05). These data demonstrate that upregulation of StAR is associated with hyperALDO in PAH, which promotes vascular fibrosis through a mechanism involving CTGF. Identifying StAR and/or CTGF as novel treatment target(s) to attenuate pulmonary vascular fibrosis has potential therapeutic implications for patients with PAH.
- © 2013 by American Heart Association, Inc.