Targeting Cadherin-11 Prevents Notch1-Mediated Calcific Aortic Valve Disease
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Calcific aortic valve disease (CAVD) accounts for ≈15 000 patient deaths per year in the United States, and intervention occurs only when severe stenosis requires surgical replacement of the valve. Recently, it was discovered that long noncoding RNA H19 expression silences NOTCH1 in cases of idiopathic CAVD,1 similar to the heritable form in patients with NOTCH1 mutations.2 We have previously reported that valves from idiopathic cases are enriched for the cell junction protein, cadherin-11 (CDH11),3 and that valve interstitial cells from Notch1+/− mice overexpress CDH11.4 Thus, we speculate that CDH11 is downstream of NOTCH1 receptor dysfunction and may be a hallmark in both heritable and idiopathic CAVD.5 Here, we sought to determine whether targeting CDH11, genetically or pharmacologically, would prevent CAVD in Notch1+/− mice.
Notch1+/+ and Notch1+/− mice were given a high-fat/high-cholesterol diet starting at 10 weeks. At 4 months, 10 mg/kg SYN0012, a CDH11-blocking antibody, or IgG2a isotype control was administered by intraperitoneal injection once a week for 8 …