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Endotoxin infusion in rats induces apoptotic and survival pathways in the heart

University of British Columbia

Inflammatory mediators of sepsis induce apoptosis in many cell lines. We tested the hypothesis that lipopolysacharide (LPS) injection in vivo results in induction of early apoptotic and survival pathways as well as evidence of late-stage apoptosis in the heart. Hearts were collected from control rats and at 6, 12 and 24 hours after LPS injection (4 mg/kg). After LPS injection Bax (early pro-apoptotic) mRNA increased (16% at 24 hours, p<0.05) whereas Bax protein initially decreased (35% at 6 hours, p<0.05) and then returned to baseline values by 24 hours. Six hours after LPS injection Bcl-2 (early survival) mRNA levels increased while its protein levels decreased (70%, p<0.05) and then returned to baseline levels by 24 hours. Mitochondrial cytochrome C levels decreased suggestive of mitochondrial involvement. Activation of an apoptotic pathway was confirmed by the 1000 fold increase in caspase 3 activity at 24 hours (p<0.05). TUNEL staining identified myocardial cells undergoing DNA fragmentation with significant levels occurring at 24 hours post LPS injection. Heart function in this model as measured by myocyte contractility, showed a 29% decrease in fractional shortening at 6 hours after LPS injection with a 50% improvement present by 12 hours. Heart function at 24 hours was comparable to the 12 hour time point. Thus, activation of apoptotic and survival pathways in the heart occurs during a septic inflammatory response. The presence of apoptotic pathways temporarily correlates with myocardial dysfunction.

Thesis/Dissertation

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2009-07-13

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http://hdl.handle.net/2429/10695

Experimental Medicine

University of British Columbia

UBCV

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