Targeting mitochondrial fission as a potential therapeutic for abdominal aortic aneurysm

Abstract

Aims Angiotensin II (AngII) is a potential contributor to the development of abdominal aortic aneurysm (AAA). In aortic vascular smooth muscle cells (VSMCs), exposure to AngII induces mitochondrial fission via dynamin-related protein 1 (Drp1). However, pathophysiological relevance of mitochondrial morphology in AngII-associated AAA remains unexplored. Here, we tested the hypothesis that mitochondrial fission is involved in the development of AAA. Methods and results Immunohistochemistry was performed on human AAA samples and revealed enhanced expression of Drp1. In C57BL6 mice treated with AngII plus β-aminopropionitrile, AAA tissue also showed an increase in Drp1 expression. A mitochondrial fission inhibitor, mdivi1, attenuated AAA size, associated aortic pathology, Drp1 protein induction, and mitochondrial fission but not hypertension in these mice. Moreover, western-blot analysis showed that induction of matrix metalloproteinase-2, which precedes the development of AAA, was blocked by mdivi1. Mdivi1 also reduced the development of AAA in apolipoprotein E-deficient mice infused with AngII. As with mdivi1, Drp1+/− mice treated with AngII plus β-aminopropionitrile showed a decrease in AAA compared to control Drp1+/+ mice. In abdominal aortic VSMCs, AngII induced phosphorylation of Drp1 and mitochondrial fission, the latter of which was attenuated with Drp1 silencing as well as mdivi1. AngII also induced vascular cell adhesion molecule-1 expression and enhanced leucocyte adhesion and mitochondrial oxygen consumption in smooth muscle cells, which were attenuated with mdivi1. Conclusion These data indicate that Drp1 and mitochondrial fission play salient roles in AAA development, which likely involves mitochondrial dysfunction and inflammatory activation of VSMCs.

78 kDa Glucose-Regulated Protein Attenuates Protein Aggregation and Monocyte Adhesion Induced by Angiotensin II in Vascular Cells

“…Prolonged UPR has been shown to be proinflammatory [32,33].Therefore, we next sought to determine if leukocyte adhesion to AngII exposed VSMCs could be mitigated by the ER chaperone treatment. THP-1 monocyte recruitment assay with VSMCs was utilized to simulate vascular inflammation [34]. The VSMCs stimulated for 48 h with AngII showed higher THP-1 adhesion compared with the baseline condition, which was significantly attenuated by GRP78 overexpression (Figure 4).…”

“…THP-1 monocyte adhesion assay was performed as previously described [34]. VSMCs were plated in 24 well dishes and serum starved for 48 h at 80-90% confluency.…”

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

“…DRP1 has been found enriched in calcified regions of human carotid arteries, and mice heterozygous for DRP1 deletion are resisted to vascular calcification in an atherosclerosis model (Rogers et al, 2017). It should be noted that inhibition of mitochondrial fission by mdivi-1 or by expression of DRP1K38A can prevent VSMCs from over proliferation at high glucose level (Maimaitijiang et al, 2016), AngII infusion (Cooper et al, 2020) or PDGF stimulation (Salabei and Hill, 2013;Wang et al, 2015). In addition, DRP1K38A transgene in mice displayed a protective effect on intimal vascular proliferation after vascular injury (Wang et al, 2015).…”

Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics

“…Nox-derived ROS Nox1/2 [70,71] in vitro Nox-derived ROS MEK/ERK, p38, Akt [72] in vitro Nox-derived ROS Rac1 [73] in vitro Mitochondrial ROS Complex I/II [68] in vitro Sm22α PI3K/Akt [74] in vivo p53 Complex IV [69] in vivo Mitochondria fission Drp1 [75] Figure 3. Inhibitory signaling events against AngII/AT1R-mediated senescence in VSMC.…”

“…In abdominal aortic smooth muscle cells, AngII stimulated Drp1 activity and mitochondrial fission via ERK1/2-dependent Drp1 Ser616 phosphorylation. Inhibiting Drp1 activity in mice further attenuated AngII-induced AAA development which was associated with reduction of aortic senescence assessed by SA-βgal and p16 induction [75]. In endothelial cells, Drp1 also mediates NF-κB activation [104].…”