Abstract
Common causes for heart failure (HF) include hypertension and myocardialinfarction (MI). Although inflammation is associated with HF, the processes that
initiate myocardial inflammation remain unknown. The immune sensor, toll-like
receptor (TLR)-9 is involved in pressure overload-induced myocardial
inflammation and cardiac remodelling. Various cellular pathways are activated
after pressure overload, including the β-adrenergic receptor (β-AR) signalling
cascade. Furthermore, the role of TLR9-mediated inflammation after MI is yet to
be determined. Therefore, this thesis aimed to elucidate the pathophysiological
relevance of TLR9-mediated inflammation in HF induced by chronic β-AR
activation and MI.
WT and TLR9KO mice were implanted with minipumps infusing 50 mg/kg/day
isoprenaline (Iso) over 4 weeks. Cardiac dysfunction, chamber dilatation,
hypertension, heart weight gain and tachycardia were observed in Iso-infused
WT and TLR9KO mice. The extent of fibrosis, inflammation and apoptosis were
similar between WT and TLR9KO mice after Iso infusion. Interestingly, Isoinfused
TLR9KO mice exhibited improved cardiac function and reduced heart
weight gain compared to Iso-infused WT mice, suggesting that TLR9 influences
β-AR-induced cardiac remodelling. Further investigation of the Iso infusion
model found that Iso-induced cardiac dysfunction and tachycardia were
recoverable 1 day after removal of Iso. Whilst metabolism, oxidative stress,
calcium signalling and mitochondrial structure were maintained after Iso
infusion, increased degradation of IκB was observed.
To evaluate the role of TLR9-mediated inflammation after MI, WT and TLR9KO
mice were subjected to coronary artery ligation. Interestingly, the mortality of
TLR9KO mice 4 days after MI was significantly higher than WT mice due to
cardiac rupture. There were no differences in inflammation between MIoperated
WT and TLR9KO mice. However, decreased mRNA of Timp1 and
fewer fibroblasts and myofibroblasts were observed in MI-operated TLR9KO
mice compared to WT mice, suggesting a life-preserving role of TLR9 in tissue
repair.
These findings indicate novel roles of TLR9, independent of its inflammatory
function and demonstrate its double-edged nature within the failing heart.
| Date of Award | 2016 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Kinya Otsu (Supervisor), Frederic Geissmann (Supervisor) & Alison Brewer (Supervisor) |