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Thyroid hormone induces vascular relaxation through VASP phosphorylation at serine 239 : a potential therapeutic approach to treat diabetic vascular dysfunction
Author(s) -
Samuel Sherin,
Gerdes A. Martin,
CarrilloSepulveda Maria Alicia
Publication year - 2016
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.30.1_supplement.1282.11
Subject(s) - vascular smooth muscle , endocrinology , medicine , enos , phosphorylation , diabetes mellitus , vasodilation , nitric oxide , hormone , endothelial dysfunction , biology , microbiology and biotechnology , nitric oxide synthase , smooth muscle
Vascular complications are the major problem faced by diabetic patients. Impairment of vasorelaxation is the earliest manifestation of diabetic vascular dysfunction. Anti‐hyperglycemic drugs have significantly improved the quality of life of these patients; however it still does not prevent the onset of vascular complications. Alternative therapeutic strategies are clearly needed. Recent studies have indicated that thyroid hormone, triiodothyronine (T3), has anti‐diabetic effects. T3 is known to rapidly relax vascular smooth muscle cells (VSMCs) via mechanisms that involve nitric oxide (NO). However, the endothelial‐smooth muscle cells interaction mechanisms have not been well explored. Recently, a correlation between VASP phosphorylation at serine 239, a substrate for cGMP‐dependent protein kinase (PKG), and VSMC relaxation has been demonstrated. We hypothesized that a signaling pathway through NO/cGMP/PKG/VASP is involved in T3‐induced vascular relaxation, which in turn can offer an adjunct treatment to vascular dysfunction during diabetes. In vitro studies showed that human endothelial cells (EC) treated with 0.1uM T3 for short‐time (2 to 60 minutes) display significant phosphorylation of Akt (1.7±0.1 fold of increase vs. unstimulated cells) and eNOS (1.9 ±0.2 fold of increase vs. unstimulated cells). Moreover, T3 robustly increased levels of NO (2.3±0.2 fold of increase vs. unstimulated cells; p<0.001) in EC. Additionally, T3 treatment increased phosphorylation of VASP at serine 239 in human VSMCs (2.0 ± 0.2 fold of increase vs. control; p<0.05), which was diminished in the presence of 1uM KT5823, a selective PKG inhibitor. Rat aortas incubated with 0.1uM T3 for 24 hours showed a significant increase in PKG expression (1.8±0.1 fold of increase vs. unstimulated aortas; p<0.05). Endothelium‐dependent and – independent relaxation was assessed in rat aortas treated with 0.1uM T3 for 20 minutes. Aortas treated with T3 exhibited greater sensitivity (EC50) to acetylcholine (EC50 value: 7.80±0.07 vs. 7.10±0.05 control, p<0.0001) and sodium nitroprusside (EC50 value: 8.12±0.03 vs. 7.6±0.02, p<0.0001). T3‐induced vasorelaxation independent of endothelium was partially reduced in the presence of 1uM KT5823 (EC50 value: 7.8±0.02, p<0.05). Aortas from male db/db mice, a model of type 2 diabetes, displayed decreased levels of VASP phosphorylated at serine 239 (2.7 ± 0.1 fold of decrease vs. control; p<0.0001). Moreover, impaired relaxation response to Ach observed in db/db aortas was improved with T3 (0.1μM) incubation. Our results suggest a novel NO/PKG/VASP molecular mechanism underlying T3‐induced vascular relaxation. Therefore, strategies utilizing T3 in safe dose pose a promising approach as an adjunct therapy to treat vascular dysfunction in diabetes.Relaxation responses to acetylcholine are increased in aortic rings pre‐treated with T3 (0.01 uM). Values are mean±SD (n=7).Relaxation responses to sodium nitroprusside are increased in aortic rings pre‐treated with T3 (0.01 uM). Values are mean±SD (n=5).Schematic hypothesis