Abstract 13526: Transgenic Mice Lacking Sirt1 or Sirt1 Catalytic Activity Exhibit Greater Susceptibility to Pulmonary Hypertension in Response to Chronic Hypoxia
Introduction: Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary artery pressure, leading to right ventricle hypertrophy and ultimately heart failure and death. Sirt1 is an NAD+ dependent deacetylase that has been strongly implicated in maintaining EC homeostasis in systemic vessels, but little is known about its role in the lung vasculature. The purpose of this study was to investigate the role of Sirt1 in PH induced by chronic hypoxia (CH). Hypothesis: Sirt1 maintains endothelial function and protects against pulmonary vascular remodeling in response to CH.
Methods: Female Sirt1 KO, Sirt1YY(H355Y point mutation lack catalytic activity) and their wild type littermates were exposed to normoxia (N) or CH (9-10% O2). Hemodynamic assessments, lung tissue collection and hematocrit levels were obtained at three weeks.
Results: Exposure of Sirt1YY mutant mice to CH for 3 weeks resulted in a marked increase in right ventricle systolic pressure (RVSP) compared to their WT littermates exposed to the same conditions (Figure 1) with significantly greater RV remodeling, measured by the RV/LV+S weight ratio (0.55±0.03 Sirt1YY vs. 0.40±0.01 WT, n=9-19; p< 0.001). Similarly, the Sirt1 null mice showed exaggerated responses to CH (Figure 1) (RV/LV+S 0.64±0.04 Sirt1 KO vs. 0.43±0.01 WT, n=7-19; p<0.001). Hypoxia-induced pulmonary smooth muscle cell hyperplasia and perivascular cell infiltration were also exacerbated in both mutant strains. Interestingly, there was a profound increase in the hematocrit in Sirt1 KO compared to wild type animals (73±4.8% vs. 57.6±0.8%, n=7 both; p<0.01), which was strongly correlated with increases in RVSP.
Conclusion: Sirt1 protects against hypoxia-induced PH. In addition to its well known role in maintaining endothelial function, Sirt1 may regulate HIF-EPO signalling, and the increase in PH in response to CH in the KO mice may in part be due to marked increases in red cell production and blood viscosity
- © 2012 by American Heart Association, Inc.