TY - JOUR
T1 - Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress
AU - Rogers, Maximillian A.
AU - Maldonado, Natalia
AU - Hutcheson, Joshua D.
AU - Goettsch, Claudia
AU - Goto, Shinji
AU - Yamada, Iwao
AU - Faits, Tyler
AU - Sesaki, Hiromi
AU - Aikawa, Masanori
AU - Aikawa, Elena
N1 - Funding Information:
This study was supported by a research grant from Kowa Company, Ltd. (Tokyo, Japan, to M. Aikawa) and the National Institutes of Health grants (R01HL114805 and R01HL136431 to E. Aikawa)
PY - 2017/7/21
Y1 - 2017/7/21
N2 - Rationale: 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. Objective: To examine the effects of osteogenic promoting conditions on DRP1 and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results: DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells increased DRP1 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 DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 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 Drp1 deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. Conclusions: 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.
AB - Rationale: 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. Objective: To examine the effects of osteogenic promoting conditions on DRP1 and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results: DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells increased DRP1 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 DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 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 Drp1 deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. Conclusions: 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.
KW - atherosclerosis
KW - collagen
KW - mitochondria
KW - myocytes, smooth muscle
KW - oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85020536425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020536425&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.116.310293
DO - 10.1161/CIRCRESAHA.116.310293
M3 - Article
C2 - 28607103
AN - SCOPUS:85020536425
VL - 121
SP - 220
EP - 233
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 3
ER -