Preeclampsia (PE), a hypertensive disease of pregnancy, occurring at or after gestational week 20. PE can have life threating consequences for both the mother and the baby. PE is a highly heterogenous disease which makes it challenging to identify any effective therapeutic interventions. We previously discovered three molecular subclasses of PE disease. One of these subclasses is characterized by heightened placental inflammation (inflammation-driven PE). Since it is a newly identified form of PE, we currently do not know about the molecular mechanisms driving this inflammation-driven form of PE. Interestingly, we have observed that placentas from this inflammatory PE subclass uniquely express higher levels of NAD+ consuming enzymes- PARPs - and thus exhibit a decrease in NAD+ content. NAD+ is a regulator of cellular energy metabolism and mitochondrial function. Several studies in the non-pregnant populations suggested that pro-inflammatory disease conditions can trigger hyperactivation of NAD+ consuming enzymes causing a depletion in total NAD+ content, leading to mitochondrial dysfunction and organ failure. Thus, we tested the hypothesis that NAD+ depletion causes placental mitochondrial dysfunction in the inflammatory subclass of PE and that boosting NAD+ could prevent development of this form of placental disease. We aimed to profile PARP activity, NAD+ availability, and mitochondrial health in human cases of all three PE subclasses. We examined the causal relationship between inflammation and dysregulated NAD+ signalling in both an in vitro human trophoblast culture model and in a rodent model of inflammation-driven PE. We also evaluated the therapeutic potential of NAD+ booster, nicotinamide riboside (NR) to improve placental health and function in the rodent model of inflammation-driven PE. Our results suggest that along with increased activity of PARP enzymes and decreased NAD+ levels, human inflammatory PE placentas also exhibit decreased levels of mitochondrial proteins and increased oxidative DNA damage. Using an in vitro human placental (HTR8 cell line) inflammation model we showed that increasing NAD+ under an inflammatory condition improved trophoblast mitochondrial and cellular function. Using an in vivo LPS induced rat model of inflammation-driven PE, we demonstrated that NAD+ boosting during pregnancy improved placental mitochondrial function, reduced inflammation and oxidative stress. This subsequently resulted in improved pregnancy outcomes demonstrated by reduced maternal blood pressure, increased placental/fetal weights and increased fetal survival in the LPS model. Overall, this study identifies targeting NAD+ signaling as a promising intervention for PE. NAD+ boosting through NR has been tested in non-pregnant human populations and found to be safe and effective in enhancing NAD+ levels. Thus, findings of this thesis lay the ground to test NAD+ boosting strategies in PE patients in near future.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/45441 |
| Date | 19 September 2023 |
| Creators | Jahan, Fahmida |
| Contributors | Menzies, Keir J. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
Page generated in 0.0022 seconds