Triiodothyronine Reduces Vascular Dysfunction Associated with Hypertension by Attenuating Protein Kinase G/Vasodilator-Stimulated Phosphoprotein Signaling

Abstract

Vascular dysfunction associated with hypertension comprises hypercontractility and impaired vasodilation. We have previously demonstrated that triiodothyronine (T3), the active form of thyroid hormone, has vasodilatory effects acting through rapid onset mechanisms. In the present study, we examined whether T3 mitigates vascular dysfunction associated with hypertension. To test the direct effects of T3 in hypertensive vessels, aortas from female Dahl salt-sensitive (Dahl SS) rats fed a high-salt diet (8% NaCl, HS group) and their age-matched controls fed a standard low-salt diet (0.3% NaCl, LS group) for 16 weeks were isolated and used in ex vivo vascular reactivity studies. We confirmed that the HS group exhibited a higher systolic blood pressure in comparison with the control LS group and displayed aortic remodeling. Aortas from both groups were pretreated with T3 (0.1 mM) for 30 minutes at 37°C in a 5% CO 2 incubator before functional vascular studies. T3 treatment significantly attenuated hypercontractility and improved impaired endothelium-dependent vasodilation in aortas from the HS group. These vascular improvements in response to T3 were accompanied by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 239, a vasodilatory factor of the cGMP-dependent protein kinase (PKG)/ VASP signaling pathway in vascular smooth muscle cells. Moreover, increased production of reactive oxygen species in aortas from the HS group were significantly reduced by T3, suggesting a potential antioxidant effect of T3 in the vasculature. These results demonstrate that T3 can mitigate hypertension-related vascular dysfunction through the VASP signaling pathway and by reducing vascular ROS production. SIGNIFICANCE STATEMENT This study demonstrates that triiodothyronine (T3) directly acts on vascular tone and has a beneficial effect in hypertensioninduced vascular dysfunction. T3 augmented vasodilation and diminished vasoconstriction in blood vessels from hypertensive rats in association with activation of the protein kinase G/vasodilator-stimulated phosphoprotein signaling pathway that activates vascular relaxation and exerted an antioxidant effect. Collectively, these results show that T3 is a potential vasoprotective agent with rapid action on hypertensionrelated vascular dysfunction.

Thyroid Dysfunction and Dysmetabolic Syndrome: The Need for Enhanced Thyrovigilance Strategies

“…Experimental studies indicate that administration of TH after acute myocardial infarction (AMI) may improve myocardial function by reducing the infarct size [ 17 ]. T3 can mitigate hypertension-related vascular dysfunction via its antioxidant effect [ 16 , 24 ]. However, further research is needed before TH can be therapeutically administered to patients who have had MI or patients with hypertension [ 18 ].…”

BNP as a New Biomarker of Cardiac Thyroid Hormone Function

“…Indeed, microvascular blood flow is impaired in non-cardiac patients with subclinical hypothyroidism (Baycan et al, 2007). Recent rat studies from our group have shown that in hypertension (Carrillo-Sepulveda et al, 2019) and ischemic HF (Zhang et al, 2018), aortic rings are less responsive to the vasodilator acetylcholine. Pre-incubation with T3 largely restores vessel responsiveness toward normal.…”

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

“…Samples were then analyzed for vascular remodeling using Image J software according to established protocols (Gomez-Roso et al 2009 ; Maia et al 2014 ). Image J analysis included measures of aortic wall thickness, cross sectional area (CSA), wall thickness per lumen ratio (Wm/L), and lumen diameter, as previously described (Carrillo-Sepulveda et al 2019 ). Slides were digitized using an Olympus BX53 fluorescent microscope (Olympus America, Inc., Center Valley, MA, USA), high-resolution regular light digital images were captured under high-power magnifications (× 4) using an Olympus DP72 (Olympus America, Inc., Center Valley, MA, USA).…”