Abstract 1868: The Role of Endoplasmic Reticulum Stress in β-Adrenergic Receptor Blocker Therapy of Chronic Heart Failure
Background: Reduced myocardial apoptosis has been proposed as a mechanism responsible for β-blocker therapy in chronic heart failure (CHF). Endoplasmic reticulum (ER) stress could trigger signaling cascade leading to apoptosis. However, the role of ER stress in β-blocker therapy for CHF has not been studied. This study examined ER stress in CHF and evaluated its role in β-blocker therapy in a canine model of ischemic CHF.
Methods: CHF was created by daily coronary (LAD) embolization in chronically instrumented dogs. After CHF, metoprolol (MET, 30mg/day, PO, n=6) or vehicle (n=6) was given for 12 wks. Left ventricular (LV) pressure, LVdP/dtmax, LV end-diastolic pressure (LVEDP), aortic pressure (AoP) and EF were evaluated prior to, after CHF and 12 wks after β-blocker in awake state. In terminal experiments, LV samples from these dogs and other 5 normal dogs were used to determine cellular levels of ER stress markers, phosphorylated eukaryotic initiation factor 2α (eIF2α-P) and calreticulin, by Western analysis.
Results: Hemodynamics are summarized in the Table⇓ (Mean±SE, *, p<0.05 from Baseline; †, p<0.05 from CHF; #, p<0.05 from Placebo). Compared to vehicle treated group, MET caused significantly improved cardiac function accompanied with normalization of ER stress markers. In CHF state, the phosphorylated form of eIF2α was markedly increased (6.4±2.1 vs 1.2±0.2, p<0.05) while the total cellular eIF2α protein levels were not significantly altered (data not show). MET greatly reduced the phosphorylation of eIF2α (2.8±1.1, p<0.05 vs CHF). Calreticulin, an ER chaperon, was also induced in CHF (2.8±0.4 vs 1.4±0.2, p<0.05) while normalized by MET (1.6±0.4, p<0.05 vs CHF).
Conclusion: Our data demonstrated that ischemic-induced CHF leads to increased ER stress while β-blocker improves cardiac function and reduces ER stress. The results suggest that ER stress could be cellular events upstream of apoptosis in CHF while reducing ER stress might improve cardiac function.