Three weeks of SMC CYB5R3 knockdown accelerates development of PH in SS chimeras. Chimeras testing ≥80% engraftment, assessed by Hb electrophoresis, were aged an additional 3 weeks (A-D) or 12 weeks (E-H) on regular diet before measurement of hemodynamics by closed-chest RV microcatheterization. (A) At 3 weeks following completion of tamoxifen-induced KO, RVmaxSP for SS/R3^KD (blue bar, n = 13) was increased relative to SS/R3^WT (red bar, n = 10). (B) Heart rates (HR) between knockdown and WT groups were similar (n = 13 and 10, respectively). Both RV/tibia (C) and LV+S/tibia (D) were enlarged in the knockdown group (n = 20) relative to WT (n = 14) at the 3-week time point. For the 12-week study, no differences were observed between CYB5R3 knockdown and WT groups for RVmaxSP (E) and HR (F) (n = 5 and 6, respectively). (G) RV/tibia was enlarged in the knockdown group relative to WT, whereas (H) LV+S/tibia was similar between groups (n = 5 and 7, respectively). The mean ± SEM is represented. The Student unpaired t test was used to determine statistical significance. ^&A nonparametric Mann-Whitney U test was used to determine statistical significance when F test indicated a non-Gaussian distribution of variance between groups.