MK-6482 treatment reduced pulmonary hypertension in Vhl^R200W, Irp1-KO, and double-mutant Vhl^R200W;Irp1-KO mice and diminished elevated endothelin-1 levels in all 3 mouse models. (A) RVPs measured by catheterization of lightly anesthetized mice showed significantly elevated pressures in Vhl^R200W, Irp1-KO, and Vhl^R200W;Irp1-KO mice in comparison with WT mice, and MK-6482 treatment significantly decreased the RVPs, not only in Vhl^R200W and Irp1-KO mice, but also in double-mutant Vhl^R200W;Irp1-KO mice. (B) Transthoracic echocardiography showed systolic flattening of the IVS in vehicle-treated Vhl^R200W mice, as indicated by the appearance of an abnormal D-like structure (arrows) compared with the normal convex appearance of the IVS in the WT mice. The D-like structure disappeared and the normal convex shape of the IVS reappeared upon treatment with MK-6482. Representative images from 2 animals of each group are shown. Five mice from each group were tested, except for the drug-treated Vhl^R200W;Irp1-KO group, in which 3 mice were tested. (C) Serum endothelin-1 levels were elevated in Vhl^R200W, Irp1-KO, and Vhl^R200W;Irp1-KO mice compared with the WT mice. When treated with MK-6482, the endothelin-1 levels of the mutant and double-mutant mice reverted to normal WT levels. ns, not significant, *P < .05; ***P < .001 by ordinary 1-way ANOVA (multiple comparisons). D-mutant, double-mutant Vhl^R200W;Irp1-KO mouse.