Macrophage (Drp1) Dynamin-Related Protein 1 Accelerates Intimal Thickening After Vascular Injury

Abstract

<jats:sec> <jats:title>Objective:</jats:title> <jats:p>Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynamin-related protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury.</jats:p> </jats:sec> <jats:sec> <jats:title>Method and Results:</jats:title> <jats:p>To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.</jats:p> </jats:sec>

ANT2 drives proinflammatory macrophage activation in obesity

“…For example, M1-like macrophage polarization accompanies mitochondrial fragmentation, mitophagy, and decreased mitochondrial activity (34). Pharmacological inhibition of DRP1 or genetic deletion of Drp1, the key factor for the regulation of mitochondrial fission and mitophagy, blocks M1-like macrophage polarization (35,36). Moreover, increased production of mitochondrial ROS (mtROS) or accumulation of a mitochondrial metabolite, succinate, drives M1-like macrophage polarization by stabilizing hypoxia-inducible factor 1α (HIF-1α) (37)(38)(39).…”

Coronary Endothelium No‐Reflow Injury Is Associated with ROS‐Modified Mitochondrial Fission through the JNK‐Drp1 Signaling Pathway

“…Another study revealed that reperfusion-mediated energetic crises were attenuated by mitochondrial fission suppression in a mouse model of cardiac ischemia/reperfusion injury [67]. It was also reported that intimal thickening after coronary damage was enhanced by mitochondrial fission due to dysregulated macrophage function [68,69]. Further, it was demonstrated that inflammation and apoptosis of coronary endothelial cells were reduced via inhibition of mitochondrial fission or activation of mitophagy [70].…”

oxLDL-Induced Trained Immunity Is Dependent on Mitochondrial Metabolic Reprogramming

“…In addition, gene ontology pathway analysis of upregulated genes in oxLDL-trained macrophages showed upregulation of pathways relevant to mitochondrial synthesis and function. It has previously been demonstrated that induction of mitochondrial fission in macrophages promotes atherosclerosis in mice [ 48 ], suggesting that alterations in mitochondrial fission might also be involved in the mitochondrial morphology changes in the current study. Moreover, stimulation of mitochondrial biogenesis could be (co)responsible for the observed increase in OXPHOS activity and mitochondrial size in oxLDL-trained macrophages.…”