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. Reciprocal interactions between valvular endothelial cells and interstitial cells are critical for the development of calcific aortic valve disease, but its molecular mechanisms remain elusive. We revealed previously unidentified roles of dipeptidyl pedtidase-4 (DPP-4) and insulin-like growth factor-1 as key proteins of valvular calcification process and crucial targets for protecting calcific aortic valve disease development. Endothelial dysfunction increased the DPP-4 expression and promoter binding in aortic valvular interstitial cells, with increased degradation of insulin-like growth factor-1 resulting in osteogenic differentiation of valvular interstitial cells. Treatment with a DPP-4 inhibitor was protective against the progression of aortic valve calcification in animal models of calcific aortic valve disease. We elucidated the mechanisms underlying the deleterious effects of endothelium-dependent activation of DPP-4 activity in inducing insulin-like growth factor-1deficiency, leading to valvular calcification and development of calcific aortic valve disease. The DPP-4-insulin-like growth factor-1axis is a promising therapeutic target considering favorable evidences supporting potential role of DPP-4 inhibitors in animal experiments and their availability in the current clinical practice. For successful drug repositioning of DPP-4 inhibitors, further studies are necessary to determine optimal dose and timing of medical intervention to prevent calcific aortic valve disease progression.