Biochemical and Biophysical Research Communications
Activation of AMPK/proteasome/MLCK degradation signaling axis by telmisartan inhibits VSMC contractility and vessel contraction
Graphical abstract
Introduction
Telmisartan, an angiotensin II type 1 receptor blocker (ARB), known to dampen the body’s renin-angiotensin-aldosterone system, is widely used to treat hypertension. Apart from its blood pressure-lowering effect, telmisartan exhibits various organoprotective effects [1,2]. In addition, telmisartan is reported to act as a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ), and shows its ancillary effects, including vascular protection through either PPARγ-dependent or -independent signaling pathways [3,4].
Vascular smooth muscle cells (VSMCs) comprise a large portion of blood vessels and play an essential role in the maintenance of normal vascular homeostasis [5,6]. Increased VSMC contractility and dysregulation of vasoconstrictor signaling pathway in VSMCs have been associated with the development of various vascular diseases such as hypertension, atherosclerosis, and vasospasms [7,8]. Furthermore, the central mechanism for pathological vasospasms has been recently revealed as VSMC hypercontraction, and not endothelial dysfunction, which leads to fatal vascular diseases and/or complications including coronary artery spasm and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm [9,10].
Previously, acute treatment with telmisartan (at 30 μM for 30 min in the organ bath) is reported to attenuate vasoconstriction in response to phenylephrine (PE) [11], and endothelium-dependent nitric oxide (NO) and prostanoid productions are responsible for the acute inhibitory effect of telmisartan [11]. However, direct and long-term effect of telmisartan on VSMC contractility, and its mechanism of action remain unknown. In the present study, we investigated the mechanism by which telmisartan inhibits VSMC contractility and vessel contraction in rat VSMCs and endothelium-deprived aortas.
Section snippets
Materials
Telmisartan and losartan were purchased from Cayman Chemicals (Ann Arbor, MI, USA). Fimasartan was a kind gift from Boryung Pharmaceuticals (Seoul, Korea). D-glucose, GW9662, MG-132, doxycycline, PE, and dimethyl sulfoxide (DMSO) were obtained from Sigma-Aldrich (St. Louis, MO, USA). Compound C was purchased from Calbiochem (Darmstadt, Germany). Antibodies against myosin light chain kinase (MLCK) and β-actin were purchased from Sigma-Aldrich. MLC, p-MLC-Ser19, AMP-activated protein kinase
Telmisartan attenuates PE-induced vessel contraction by decreasing MLCK expression and p-MLC-Ser19 levels through proteasomal MLCK degradation in VSMCs
Although endothelium-dependent NO and prostanoid productions have been previously reported to mediate acute inhibitory effect of telmisartan (at 30 μM for 30 min in the organ bath) on vasoconstriction [11], direct and long-term effect of telmisartan on VSMC contractility and consequent vessel contraction remain unknown. To this end, we incubated the endothelium-deprived rat aortic rings in the absence or presence of 40 μM telmisartan for 24 h ex vivo, and then performed PE-induced aortic ring
Discussion
Abnormal or hyperactive VSMC contractility is associated with the development of various vascular diseases such as hypertension, atherosclerosis, and pathological vasospasms. In this regard, coronary artery spasm is well known to play important roles in the pathogenesis of a wide range of ischemic heart diseases, including angina pectoris, myocardial infarction, and sudden cardiac death [21]. Additionally, cerebral vasospasm after aneurysmal SAH is recognized as a serious complication with a
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was supported by National Research Foundation (NRF) grants (2018R1D1A1B07050732) and the Medical Research Center Program (2015R1A5A2009124), funded by the Korean government.
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