Abstract 957: Heme Oxygenase-1 Alleviates Pathological Remodeling in Post-infarction Heart Failure
Heme oxygenase-1 (HO-1) is an important stress-response protein with anti-apoptotic effects; however, the pathophysiological role of HO-1 in chronic heart failure (HF) is unknown. We tested the hypothesis that long-term HO-1 induction imparts cardioprotective effects in the failing heart. We examined LV remodeling following permanent coronary ligation and large infarction (or sham-operation) in adult male transgenic (TG) mice with cardiac-specific HO-1 overexpression (n=48) and in non-transgenic (NTG) littermate controls (n=37). Baseline echocardiography showed no underlying cardiac phenotype in the TG mice. At 4 weeks after surgery, NTG HF hearts (vs. NTG sham) showed significantly (p < 0.05) increased:
LV size (LVEDV 78 ± 32 vs. 27 ± 6 μL) and systolic dysfunction (LVEF 54 ± 11 vs. 78 ± 8 %) by echocardiography;
hypertrophy (LV/tibia length [TL] 5.2 ± 0.6 vs. 3.6 ± 0.4 mg/mm);
oxidant stress (~2.5-fold greater protein-malondialdehyde [MDA] immunostaining);
HO-1 upregulation (~2-fold); and 5) apoptosis (by TUNEL staining, caspase-8 activation, and p53 expression).
In contrast, compared to NTG HF, HO-1 TG HF hearts had significantly less (p < 0.05) LV dilatation (LVEDV 46 ± 8 μL), systolic dysfunction (LVEF 65 ± 9 %), hypertrophy (LV/TL 4.4 ± 0.4 mg/mm), oxidative stress (~60% lower protein-MDA staining), p53 expression, and apoptosis. To explore potential anti-apoptotic mechanisms underlying the beneficial effects of HO-1 in HF, we examined mitochondrial permeability transition (MPT) pore opening in mitochondria (calcium-induced mitochondrial swelling assay) and adult cardiomyocytes (TMRM labeling and confocal imaging during mitochondrial depolarization) isolated from NTG, HO-1 TG, and HO-1 null hearts. Whereas both calcium-overload-induced mitochondrial swelling and oxidative stress-induced mitochondrial depolarization were inhibited in HO-1 TG myocytes and in NTG myocytes pretreated with recombinant HO-1, these were exacerbated in HO-1 null myocytes.
Conclusion: Cardiac HO-1 upregulation confers significant cardioprotective benefits that counteract LV remodeling, oxidative stress, and apoptosis in post-infarction HF. MPT pore stabilization may contribute to the anti-apoptotic effect of HO-1 in the failing heart.