Dipeptidyl Peptidase-4 Induces Aortic Valve Calcification by Inhibiting Insulin-Like Growth Factor-1 Signaling in Valvular Interstitial Cells.
BACKGROUND
Calcification of the aortic valve leads to increased leaflet stiffness and consequently to the development of calcific aortic valve disease. However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified that dipeptidyl peptidase-4 (DPP-4, also known as CD26) increases valvular calcification and promotes calcific aortic valve disease progression.


METHODS
We obtained the aortic valve tissues from humans and murine models (wild-type and endothelial nitric oxide synthase-deficient-mice) and cultured the valvular interstitial cells (VICs) and valvular endothelial cells from the cusps. We induced osteogenic differentiation in the primary cultured VICs and examined the effects of the DPP-4 inhibitor on the osteogenic changes in vitro and aortic valve calcification in endothelial nitric oxide synthase-deficient-mice. We also induced calcific aortic stenosis in male New Zealand rabbits (weight, 2.5-3.0 kg) by a cholesterol-enriched diet+vitamin D2 (25 000 IU, daily). Echocardiography was performed to assess the aortic valve area and the maximal and mean transaortic pressure gradients at baseline and 3-week intervals thereafter. After 12 weeks, we harvested the heart and evaluated the aortic valve tissue using immunohistochemistry.


RESULTS
We found that nitric oxide depletion in human valvular endothelial cells activates NF-κB in human VICs. Consequently, the NF-κB promotes DPP-4 expression, which then induces the osteogenic differentiation of VICs by limiting autocrine insulin-like growth factor-1 signaling. The inhibition of DPP-4 enzymatic activity blocked the osteogenic changes in VICs in vitro and reduced the aortic valve calcification in vivo in a mouse model. Sitagliptin administration in a rabbit calcific aortic valve disease model led to significant improvements in the rate of change in aortic valve area, transaortic peak velocity, and maximal and mean pressure gradients over 12 weeks. Immunohistochemistry staining confirmed the therapeutic effect of Sitagliptin in terms of reducing the calcium deposits in the rabbit aortic valve cusps. In rabbits receiving Sitagliptin, the plasma insulin-like growth factor-1 levels were significantly increased, in line with DPP-4 inhibition.


CONCLUSIONS
DPP-4-dependent insulin-like growth factor-1 inhibition in VICs contributes to aortic valve calcification, suggesting that DPP-4 could serve as a potential therapeutic target to inhibit calcific aortic valve disease progression.
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Bongkun
B
Choi
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sahmin
S
Lee
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sang-Min
SM
Kim
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eun-Jin
EJ
Lee
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sun Ro
SR
Lee
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dae-Hee
DH
Kim
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jeong Yoon
JY
Jang
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sang-Wook
SW
Kang
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ki-Up
KU
Lee
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. jksong@amc.seoul.kr ejchang@amc.seoul.kr.
Eun-Ju
EJ
Chang
From Department of Biomedical Sciences (B.C., S.-M.K., E.- J.L., S.R.L., S.-W.K., E.-J.C.), Division of Cardiology (S.L., D.- H.K., J.Y.J., J.-K.S.), and Division of Endocrinology and Metabolism, Department of Internal Medicine (K.-U.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. jksong@amc.seoul.kr ejchang@amc.seoul.kr.
Jae-Kwan
JK
Song
D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*
D007334:Insulin-Like Growth Factor I; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
calcific aortic valve disease; dipeptidyl peptidase-4; insulin-like growth factor-1; valvular interstitial cells