Background: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary artery pressure, leading to right ventricle hypertrophy and ultimately heart failure and death. Sirtuin 1 (SIRT1) is an NAD+ dependent protein deacetylase that has been strongly implicated as a crucial link between longevity, stress response and maintenance of vascular health. In this thesis, we investigated the role of SIRT1 in the pulmonary vascular hypoxic response and the pathogenesis of pulmonary hypertension (PH) working under the hypothesis that SIRT1 plays a protective role in the pulmonary vasculature and that lack of SIRT1 would lead to worsening of PH in a model of chronic hypoxia (CH).
Results: We determined that global SIRT1 knockout or SIRT1 catalytic inactivation resulted in a marked increase in right ventricle pressure and remodeling compared to wildtype mice in CH. Furthermore, hypoxia-induced erythrocytosis and pulmonary vascular remodeling were profoundly increased in both SIRT1 mouse lines. Subsequent molecular assessment revealed that SIRT1 knockout, but not inactivation, led to a significant increase in mRNA levels of hypoxia inducible factor (HIF)-1α and significantly higher activity in hypoxia, leading to elevated lactate dehydrogenase A (LDHA) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) in the lungs. Interestingly, both knockout and inactivation of SIRT1 enhanced the activity of HIF2α in the hypoxic lungs and kidneys, leading to increased erythropoietin (EPO) and plasminogen activator inhibitor-1 (PAI-1). Moreover, SIRT1 knockout or inactivation was associated with a trend towards hypoxic-independent increases in HIF3α mRNA in the lungs. Prevention of glycolytic shift using dichloroacetate (DCA) did not result in improvement in this model, yet resveratrol (RSV), a SIRT1 activator/mimic, partially prevented PH only in absence of SIRT1 activity. Finally, selective endothelial cell SIRT1 deletion was sufficient to cause worse PH in the CH model.
Conclusions: SIRT1 plays a protective role in the hypoxic response through transcriptional and non-transcriptional control of the hypoxia inducible factors, thus protecting against worse hypoxia-induced PH. SIRT1 could be a novel target for future therapies in PAH.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/37550 |
| Date | 25 April 2018 |
| Creators | Taha, Mohamad |
| Contributors | Stewart, Duncan John |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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