Endotoxin infusion in rats induces apoptotic and survival pathways in hearts

Inflammatory mediators of sepsis induce apoptosis in many cell lines. We te sted the hypothesis that lipopolysaccharide (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 ra ts and at 6, 12, and 24 h after LPS injection (4 mg/kg). Activation of an a poptotic pathway was identified by a 1,000-fold increase in caspase-3 activ ity at 24 h (P < 0.05). Confirmation of these results occurred when termina l deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) stai ning identified myocardial cells undergoing DNA fragmentation with signific ant levels at 24 h post-LPS injection. LPS also caused early proapoptotic m RNA (Bax) to increase (16% at 24 h, P, 0.05), whereas the Bax protein initi ally decreased (35% at 6 h, P, 0.05) and then returned to baseline values b y 24 h. Six hours after LPS injection, Bcl-2 (early prosurvival) mRNA level s increased, whereas its protein levels decreased (70%, P < 0.05) and then returned to baseline levels by 24 h. Mitochondrial cytochrome c levels decr eased, suggestive of mitochondrial involvement. Thus involvement of proapop totic and prosurvival pathways in the heart occurs during a septic inflamma tory response.