Autophagy induction protects the perivascular adipose tissue during hyperaldosteronism-induced hypertension

• Published in: Physiology (Bethesda, Md.) Md.), 2023-05, Vol.38 (S1)
• Main Authors: Costa, Rafael, Rodrigues, Daniel, Gonçalves, Tiago, Alves, Juliano, Awata, Wanessa, Bruder-Nascimento, Ariane, Leiria, Luiz Osório, Tostes, Rita, Bruder-Nascimento, Thiago
• Format: Article
• Language: English
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5734527

Abstract only Hyperaldosteronism (HA), characterized by an autonomous production of aldosterone, promotes increased blood pressure and cardiovascular damage. The perivascular adipose tissue (PVAT) participates of the control of vascular function and is inflamed in HA. Autophagy is a recycling process of unnecessary or dysfunctional components and it is important for inflammatory tolerance, but whether the autophagic flux is dysregulated in the PVAT during HA, which would contribute to the inflammation and dysfunction of this tissue, is still to be elucidated. Herein, we hypothesize that treatment with autophagy inducer will rescue the autophagic unbalance, subsequently decreasing inflammation, and improving PVAT function during HA. 10-12-weeks-old male C57BL/6J mice were infused with aldosterone for 14 days (600ug/Kg/day via osmotic mini-pump). Vascular function was studied in PVAT-intact thoracic aortae and blood pressure was analyzed by the tail-cuff. Brown adipocyte cells (WT1) were used to evaluate the molecular mechanisms by which HA induces PVAT dysfunction. HA promoted an increase in systolic blood pressure [mmHg – before HA: 123.8±0.9 vs. after HA: 149.5±1.1]. Furthermore, PVAT decreased the contractile response [Emax (% KCl)] in control arteries [Control PVAT (-): 137.2±1.9 vs. Control PVAT (+): 107.4±2.7], whereas HA promoted loss of PVAT anti-contractile effect [HA PVAT (-): 159.9±2.9 vs. HA PVAT (+): 164.1±3.4]. We found that PVAT from HA mice presents an unbalance in LC3II/LC3I ratio, an important autophagy marker, inflammation, characterized by elevated TNF-α, IL-6, IL-1β, IL-17, and IFN-γ gene expression, and elevated reactive oxygen species (ROS). To induce autophagy, we treated mice with TB-peptide (16mg/Kg/day via ip for 7 days). TB-peptide partially improved the PVAT function of mice with HA [HA PVAT (+): 122.5±4.1]. On mechanistic levels, aldosterone (100nM, 12-96 h) induced an oscillatory autophagy flux in WT1 cells, characterized by an initial increase in LC3II/LC3I ratio at 12 and 24 h, followed by a decrease at 48 and 96 h. These effects were not observed in the presence of the mineralocorticoid receptor antagonist (Eplerenone, 1μM). Aldosterone also led to the expression of pro-inflammatory genes (TNF-α, IL-6, IL-1β, IL-17, and IFN-γ) and elevated ROS, such effects were prevented by inducing autophagy with TB-peptide. In summary, these findings reveal a new mechanism in vascular injury associated with HA, aldosterone impairs autoph