Rogers Maximillian A, Maldonado Natalia, Hutcheson Joshua D, Goettsch Claudia, Goto Shinji, Yamada Iwao, Faits Tyler, Sesaki Hiromi, Aikawa Masanori, Aikawa Elena
From the Center for Interdisciplinary Cardiovascular Sciences (M.A.R., N.M., J.D.H., C.G., S.G., I.Y., T.F., M.A., E.A.) and Center for Excellence in Vascular Biology (M.A., E.A.), Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD (H.S.).
Circ Res. 2017 Jul 21;121(3):220-233. doi: 10.1161/CIRCRESAHA.116.310293. Epub 2017 Jun 12.
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.
线粒体变化发生在细胞分化和心血管疾病过程中。动力相关蛋白1（DRP1）是线粒体分裂的关键调节因子。我们假设DRP1在心血管钙化中起作用，心血管钙化是一个涉及细胞分化的过程，也是一个有大量未满足需求的主要临床问题。
研究促成骨条件对DRP1的影响，以及DRP1抑制是否会改变心血管钙化的发展。
通过免疫组织化学检查发现，DRP1在人颈动脉钙化区域富集。原代人血管平滑肌细胞的成骨分化增加了其表达。在经历成骨分化的人平滑肌细胞中抑制DRP1可减弱基质矿化、细胞骨架重排、线粒体功能障碍，并减少I型胶原蛋白分泌和碱性磷酸酶活性。在钙化的人主动脉瓣中观察到DRP1蛋白，RNA干扰减少了原代人瓣膜间质细胞钙化。在一种前蛋白转化酶枯草杆菌蛋白酶/kexin 9型功能获得性动脉粥样硬化模型中，缺失杂合子的小鼠未表现出血管病理改变。然而，当通过氧化应激诱导矿化时，DRP1抑制可减弱小鼠和人平滑肌细胞钙化。缺失杂合子的小鼠股骨骨密度未改变，DRP1抑制可减弱人骨成骨细胞中氧化应激介导的功能障碍。
我们证明了DRP1在调节胶原蛋白分泌和心血管钙化方面的新功能，这是一个探索新疗法以改变心血管疾病中细胞纤维钙化反应的潜在发展的新领域。我们的数据还支持线粒体动力学在调节氧化应激介导的动脉钙积累和骨质流失中的作用。
