Sirtuin-1 (Sirt1) is an NAD+-dependent deacetylase that is strongly implicated in maintenance of endothelium homeostasis. We have shown that pulmonary hypertension (PH) in response to chronic hypoxia (CH) is exaggerated in Sirt1 deficient mice. Since the estrogen receptor has been identified as a target of Sirt1 deacetylation, we hypothesized that the protective effect of female sex in CH is dependent on Sirt1 activity.
Male and female mice lacking Sirt1 catalytic activity (sirt1Y/Y) and their wild type (WT) littermates were exposed to chronic hypoxia (CH; 10% O2) for 21 days.
Right ventricular hypertrophy at 3 weeks of CH was significantly lower in female (RV/LV+S =0.41±0.01) compared to male WT mice (0.47±0.03; n>8 /group, p< 0.05), whereas right ventricle systolic pressures (RVSP) were similar (29±1 and 31±2 mmHg, respectively). The sex difference in RV remodeling was lost in mutant mice deficient in Sirt1 activity, and both male and female sirt1Y/Y mice exhibited similar exaggerated increases in RVSP (39±3 vs. 40±2mmHg, respectively) and RVH (0.54±0.02 vs. 0.55±0.02; n>16/group) at 3 weeks. Interestingly, WT female mice also exhibited more modest increases in hematocrit levels in response to CH compared to males (59±1 vs. 65±1%, respectively; n>13/group, p<0.001), which was lost in sirt1Y/Y mice (71±2 vs.71±1%, respectively; n>12/group).
Lack of Sirt1 activity abolished the protective effect of female sex on RV remodeling and erythrocytosis in the CH model of PH, consistent with a role of Sirt1 in moderating the hypoxic response, most likely through estrogen signaling.