496 Transgenic Mice Lacking Sirt1 Catalytic Activity Exhibit Greater Susceptibility to Pulmonary Hypertension in Response to Chronic Hypoxia

Abstract

Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary artery pressure, leading to right ventricle hypertrophy and ultimately heart failure and death. Pulmonary endothelial cell (EC) injury and apoptosis appear to be triggers for reactive vascular cell proliferation leading to narrowing and obliteration of distal lung arterioles. Sirt1 is a 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 catalytic activity in PH. Sirt1Y/Y (H355Y point mutation) animals possess a Sirt1 protein lacking catalytic activity. Exposure of mutants (Sirt1Y/Y) to simulated normobaric hypoxia (9-10% O2) for 3 weeks resulted in a significant increase in right ventricle systolic pressure (RVSP) compared to their WT littermates exposed to the same conditions (42.9±2.3Sirt1Y/Y vs. 28.8±1.3WT; n=9 and 12 respectively, p<0.001, Figure 1 below). Furthermore, mutant animals showed significantly greater RV remodeling, measured by the RV/LV+S weight ratio (0.55±0.03 Sirt1Y/Y vs. 0.40±0.01 WT, p< 0.001) compared to the wild type littermates. In addition, hypoxia-induced pulmonary smooth muscle cell hyperplasia and perivascular cell infiltration seemed to be exacerbated in the mutant mice. Sirt1 protects against hypoxia-induced PH. This protection is most likely mediated through its well described role in maintenance of endothelial function and inhibition of apoptosis in response to stressors such as hypoxia.