Targeting Mitochondrial Fission as a Potential Therapeutic for Abdominal Aortic Aneurysm.

AIMS: Angiotensin II is a potential contributor to the development of abdominal aortic aneurysm (AAA). In aortic vascular smooth muscle cells, exposure to angiotensin II induces mitochondrial fission via dynamin-related protein 1 (Drp1). However, pathophysiological relevance of mitochondrial morphology in angiotensin II-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 angiotensin II 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 angiotensin II. As with mdivi1, Drp1+/- mice treated with angiotensin II plus β-aminopropionitrile showed a decrease in AAA compared to control Drp1+/+ mice. In abdominal aortic vascular smooth muscle cells, angiotensin II induced phosphorylation of Drp1 and mitochondrial fission, the latter of which was attenuated with Drp1 silencing as well as mdivi1. Angiotensin II also induced vascular cell adhesion molecule-1 expression and enhanced leukocyte 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 vascular smooth muscle cells. TRANSLATIONAL PERSPECTIVES: Mitochondrial fission/fusion regulation is critical to maintain mitochondrial homeostasis. A shift toward mitochondrial fission is associated with a variety of cardiovascular diseases. A GTPase, Drp1 is known to mediate mitochondrial fission and we found evidence of Drp1 dysregulation in human and mouse abdominal aortic aneurysms (AAA). The results from the present study demonstrate that pharmacological as well as genetic inhibition of mitochondrial fission via Drp1 prevents AAA formation and vascular smooth muscle aneurysmal phenotype in mouse models of the disease. These data indicate that intervening in this pathway may have therapeutic potential for treating AAA.