Mitochondrial Fission of Smooth Muscle Cells Is Involved in Artery Constriction

Abstract

H ypertension is one of the most common worldwide diseases and is a major risk factor for a variety of cardiovascular and renal events, including myocardial infarction, stroke, heart failure, and end-stage renal disease. 1 The latest survey shows that hypertension accounts for 7% of global disability adjusted life years and 9.4 million deaths in 2010.2 Therefore, the molecular mechanisms underlying hypertension and the antihypertensive therapies have always been the topics in cardiovascular fields.Mitochondria are dynamic organelles and change their morphology through fission and fusion processes named as mitochondrial dynamics.3 Defects in mitochondrial dynamics are implicated in multiple cardiovascular diseases, for instance, the increased mitochondrial fission contributes to the impairment of endothelial function in diabetes mellitus and the hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension. 4,5 More interestingly, Hong et al 6 show that mitochondrial fission is crucial for O 2 -induced ductus arteriosus constriction and closure at birth in human and rabbits. By using novel digital image processing/single particle tracking techniques, Giedt et al 7 show that mitochondria in endothelial cells continuously undergo fusion/fission, indicating that the onset of biological function related to mitochondrial dynamics should be prompt without needing the transcription and translation processes of mitochondrial dynamic-related proteins. Therefore, we speculate that interfering mitochondrial dynamics could show acute effects on the vascular function. In the present work, we investigate the effects of acute inhibition of mitochondrial fission on the constriction and relaxation of arteries and the underlying mechanisms. We find for the first time that mitochondrial fission of smooth muscle cells is involved in artery constriction, revealing a novel mechanism for vasoconstriction and providing a potential therapeutic target for hypertension. Abstract-Mitochondria

Mitochondrial Fission Inhibitors Suppress Endothelin-1-Induced Artery Constriction

“…Drp1 is mitochondrial fission related protein and mdivi-1 is a Drp1 selective inhibitor which is widely used as a pharmacologic tool to inhibit mitochondrial fission process [9, 10, 19, 20]. Mdivi-1 (1-10 µM) induced concentration-dependent relaxation in endothelium-intact rat mesenteric arteries pre-contracted with ET-1 (4 nM).…”

“…We further used another Drp1 inhibitor dynasore [10, 21] to confirm the role of mitochondrial fission in artery constriction. Similarly to the effects of mdivi-1, dynasore relaxed the ET-1 induced pre-contraction, and dynasore pretreatment for 30 min prevented the constriction induced by ET-1 in rat mesenteric arteries with intact and denuded endothelium (Fig.…”

“…The experiments were carried out according to our previous works [10, 16, 17]. The rats were sacrificed after anesthetized with sodium pentobarbitone.…”

“…The experiments were carried out according to our previous works [10]. Selected samples (aorta tissue) were incubated with ET-1 (4 nM) for 15 min, or pre-incubated with mdivi-1or Y27632 for 30 min, then treated with ET-1 (4 nM) for 15 min.…”

“…Because mitochondria continuously change their morphology by undergoing fusion and fission, we speculate that interfering mitochondrial dynamics could show acute effect on the vascular function. Our previous work found that mitochondrial fission inhibition by using mitochondrial fission inhibitors inhibited phenylephrine- and high K + -induced vasoconstriction [10]. We further used typical vasorelaxants verapamil and phentolamine to demonstrate that artery relaxation was coupled to inhibition of mitochondrial fission in arterial smooth muscle cells [11].…”