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Adiponectin Attenuates Hypertension‐Induced Vascular Remodeling through NHE‐1 Activity and LKB1/AMPK Signaling
Author(s) -
Ghantous Crystal M,
Radwan Zeina,
Farhat Rima,
Ghali Rana,
Chaaya Nancy,
Sabra Ramzi,
Zeidan Asad
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.32
Subject(s) - ampk , medicine , endocrinology , adiponectin , vascular smooth muscle , western blot , leptin , chemistry , protein kinase a , phosphorylation , biochemistry , obesity , smooth muscle , insulin resistance , gene
Hypertension leads to vascular remodeling, affects circulating levels of leptin and adiponectin (APN), and is associated with increased sodium hydrogen exchanger isoform‐1 (NHE‐1) activity. The aim of this study is to investigate the vascular protective effects of APN during hypertension. Hypothesis Hypertension‐induced vascular smooth muscle cell (VSMC) remodeling is mediated by NHE‐1 activity, LKB1/AMPK signaling and attenuated by high APN/leptin ratio. Methods In order to study the effect of hypertension on VSMC remodeling, the in vivo rat model of angiotensin II (Ang II) infusion for 14 days and the in vitro model of mechanically stretching the rat portal vein (PV; with 1.2 gr weights due to the force‐length relationship normalized to the human force of stretch during hypertension and the longitudinal orientation of its VSMCs) were used. APN (10 μg/ml) and the selective NHE‐1 inhibitor cariporide (10 μM) were added to blood vessels. Activation of ERK1/2, AMPK and LKB1 in VSMCs was evaluated by Western blot. Leptin and APN expression was studied by Western blot, while ROS production was assessed by DHE staining. Results Stretching the PV for 10 min increased p‐ERK1/2 by 2.10 ± 0.25 fold (n=5, p<0.05) in VSMCs (as compared to unstretched PVs), while cariporide and APN attenuated stretch‐induced ERK1/2 phosphorylation. Mechanical stretch for 10 min significantly decreased LKB1 and AMPK activation by 0.44 ± 0.14 and 0.34 ± 0.07 fold, respectively (n=6, p<0.05). This effect was attenuated by cariporide, while APN increased p‐LKB1 and p‐AMPK in stretched PVs to 1.0 ± 0.11 and 0.60 ± 0.04 fold respectively (n=4, p<0.05). Ang II‐infusion for 14 days increased leptin (1.48 ± 0.12 fold, n=4 p<0.05), decreased APN (0.86 ± 0.04 fold, n=6, p<0.05), and increased ROS (3.46 ± 0.07 fold, n=3, p<0.05) in PVs. Similar results were observed in the aortas of Ang II‐infused rats (leptin: 1.83 ± 0.36 fold; APN: 0.79 ± 0.06 fold; ROS: 1.54 ± 0.12 fold, n= 5, p<0.05) compared to sham‐operated rats. Conclusion APN attenuates mechanical stretch‐induced VSMC remodeling by activating the LKB1‐AMPK axis and inhibiting ERK1/2, which are mediated by NHE‐1 activity. Moreover, hypertension‐induced vascular remodeling is associated with higher leptin synthesis, lower APN synthesis, and higher ROS production in VSMCs. Support or Funding Information This work was supported by Medical Practice Plan (MPP), Faculty of Medicine at AUB, to AZ.