01 March 2017 by Mohamad Taha

Sirt1 activity is necessary for the protective effects of the female sex in the response to chronic hypoxia: a role for Sirt1 in estrogen signaling

Background

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.   

Methods

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.  

Results

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).

Conclusions

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.

Key Contributors

Mohamad Taha1,3, Yupu Deng1, Michael W. McBurney2,4 and Duncan J. Stewart1,3 1. Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute 2. Cancer Therapeutics Program, Ottawa Hospital Research Institute 3. Department of Cellular and Molecular Medicine, University of Ottawa 4. Department of Biochemistry, Microbiology and Immunology, University of Ottawa


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