Aldosterone Activates Autophagy To Increase Fibroblast Collagen Synthesis and Vascular Stiffness

Abstract

Hyperaldosteronism is associated with increased arterial stiffness; however, the contribution of fibroblasts to this response remains unknown. Accordingly, we treated human aortic fibroblasts (HAoF) with aldosterone (ALDO) (10−7 mol/L) for up to 72 h or vehicle control (V). Compared to V, ALDO increased transforming growth factor‐β (TGFβ) expression by 2.5 ± 0.2‐fold (p<0.01) and collagen III levels by 252% (p<0.01) in a time‐dependent manner. Increased TGFβ expression was associated with activation of autophagy as shown by lipation of LC3BI to LC3BII (p<0.01). To demonstrate that autophagy modulated collagen expression, autophagy was inhibited by transfecting cells with beclin1 siRNA. Inhibition of autophagy led to a 78% decrease (p<0.01) in collagen III expression without influencing TGFβ levels. To confirm these findings in vivo, C57Bl/6 mice were infused with ALDO (50 μg/kg/d) or V for 21 days. In ALDO‐treated mice, aorta TGFβ and LC3BII expression were increased with a concomitant 3.5 ± 0.5 ‐ fold (p<0.01) increase in perivascular collagen deposition. This was associated with an increase in pulse wave velocity (288.4 ± 22.4 vs. 389.6 ± 19.8 cm/sec, p<0.01), a marker of arterial stiffness, in ALDO‐treated mice. These data indicate that ALDO increases perivascular collagen deposition and vascular stiffness through a mechanism that involves activation of autophagy in fibroblasts.