Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

Mitochondrial changes occur during cell differentiation and cardiovascular disease. DRP1 (dynamin-related protein 1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical prob...

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Published inCirculation research Vol. 121; no. 3; pp. 220 - 233
Main Authors Rogers, Maximillian A, Maldonado, Natalia, Hutcheson, Joshua D, Goettsch, Claudia, Goto, Shinji, Yamada, Iwao, Faits, Tyler, Sesaki, Hiromi, Aikawa, Masanori, Aikawa, Elena
Format Journal Article
LanguageEnglish
Published United States Lippincott Williams & Wilkins Ovid Technologies 21.07.2017
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Summary:Mitochondrial changes occur during cell differentiation and cardiovascular disease. DRP1 (dynamin-related protein 1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. To examine the effects of osteogenic promoting conditions on DRP1 and whether DRP1 inhibition alters the development of cardiovascular calcification. DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells increased expression. DRP1 inhibition in human smooth muscle cells undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for deletion did not exhibit altered vascular pathology in a proprotein convertase subtilisin/kexin type 9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human smooth muscle cell calcification. Femur bone density was unchanged in mice heterozygous for deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress-mediated arterial calcium accrual and bone loss.
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ISSN:0009-7330
1524-4571
DOI:10.1161/circresaha.116.310293