Mitochondrial Fission Inhibitors Suppress Endothelin-1-Induced Artery Constriction

Abstract

Background/Aims: Endothelin-1 is implicated in the pathogenesis of hypertension, but the underlying mechanisms remained elusive. Our previous study found that inhibition of mitochondrial fission of smooth muscle cells suppressed phenylephrine- and high K⁺-induced artery constriction. Here, we studied the effects of mitochondrial fission inhibitors on endothelin-1-induced vasoconstriction. Methods: The tension of rat mesenteric arteries and thoracic aorta was measured by using a multi-wire myograph system. Mitochondrial morphology of aortic smooth muscle cells was observed by using transmission electron microscopy. Results: Dynamin-related protein-1 selective inhibitor mdivi-1 relaxed endothelin-1-induced constriction, and mdivi-1 pre-treatment prevented endothelin-1-induced constriction of rat mesenteric arteries with intact and denuded endothelium. Mdivi-1 had a similar inhibitory effect on rat thoracic aorta. Another mitochondrial fission inhibitor dynasore showed similar effects as mdivi-1 in rat mesenteric arteries. Mdivi-1 inhibited endothelin-1-induced increase of mitochondrial fission in smooth muscle cells of rat aorta. Rho-associated protein kinase inhibitor Y-27632 which relaxed endothelin-1-induced vasoconstriction inhibited endothelin-1-induced mitochondrial fission in smooth muscle cells of rat aorta. Conclusion: Endothelin-1 increases mitochondrial fission in vascular smooth muscle cells, and mitochondrial fission inhibitors suppress endothelin-1-induced vasoconstriction.

Resolvin E1 Improves Mitochondrial Function in Human Alveolar Epithelial Cells during Severe Inflammation

“…We recently showed in a model of experimental inflammation that both inhibitors induce similar anti-inflammatory effects in human PBMC (Hecker et al, 2018). Besides another study investigating fission and endothelin-1-induced artery constriction (Chen et al, 2017), we could find no further data in the literature directly comparing these two inhibitors. As possible explanations for the observed differential effects of the two inhibitors, we assume besides a cell-typespecific phenomenon that Mdivi-1 appears to be more selective than Dynasore.…”

Mitochondrial regulation of diabetic vascular disease: an emerging opportunity

“…158 Dynasore is an additional inhibitor of GTPase activity of Drp1 that has shown an ability to inhibit endothelin-1 induced artery constriction which may be of enhanced importance in the diabetic vasculature. 159 Further fundamental work remains for the development of highly selective Drp1-Fis1 inhibitor for testing with respect to its potential efficacy in the treatment of diabetic vascular disease.…”

Effects of Puerarin on Clinical Parameters, Vascular Endothelial Function, and Inflammatory Factors in Patients with Coronary Artery Disease

“…ET-1 is a vasoconstrictor secreted by vascular endothelium, and it is also involved in the pathophysiological process of multiple disease [18,19]; for example, ET-1 promotes cell proliferation of vascular smooth muscle and induces platelet aggregation [20]. NO takes part in regulating the vasodilatation of endothelial cells and cardiovasculare protection through inhibiting the adhesion and aggregation of platelets and monocytes to endothelium [21].…”