Division of Cardiovascular Medicine, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, ACB, Third Floor, 550 S Jackson St, Louisville, KY 40202, USA.
Circulation. 2010 May 4;121(17):1912-25. doi: 10.1161/CIRCULATIONAHA.109.905471. Epub 2010 Apr 19.
Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.
Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis.
HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.
血红素加氧酶-1（HO-1）是一种诱导应激反应的蛋白，具有抗氧化和抗细胞凋亡作用。然而，其在心脏重构和慢性心力衰竭（HF）中的病理生理学作用尚不清楚。我们假设在 HF 中诱导 HO-1 可减轻病理性重构。
成年雄性非转基因和心肌特异性 HO-1 转基因小鼠接受假手术或冠状动脉结扎以诱导 HF。结扎 4 周后，非转基因 HF 小鼠出现梗死后左心室（LV）重构和功能障碍、肥大、纤维化、氧化应激、细胞凋亡和毛细血管密度降低，非梗塞心肌中 HO-1 表达增加 2 倍。与非转基因小鼠相比，HO-1 转基因 HF 小鼠梗死后的存活率显著提高（94%对 57%），LV 扩张程度降低（舒张末期容积，46+/-8 对 85+/-32 微升），机械功能障碍（射血分数，65+/-9%对 49+/-16%），肥大（LV/胫骨长度 4.4+/-0.4 对 5.2+/-0.6mg/mm），间质纤维化（11.2+/-3.1%对 18.5+/-3.5%）和氧化应激（组织丙二醛减少 3 倍）。此外，HF 中的心肌特异性 HO-1 过表达促进了组织新血管形成，并改善了心肌 p53 表达（减少 2 倍）和细胞凋亡。在分离的线粒体中，HO-1 以一氧化碳（CO）依赖的方式抑制线粒体通透性转换，并被 CO 供体三羰基氯（甘氨酸）钌（II）（CORM-3）再现。HO-1 衍生的 CO 还可防止 H2O2 诱导的心肌细胞凋亡和细胞死亡。最后，体内用 CORM-3 治疗可减轻梗死后 LV 重构、p53 表达和细胞凋亡。
在衰竭的心脏中诱导 HO-1 是一种重要的心脏保护适应，可抵抗病理性 LV 重构，这种作用至少部分是通过 CO 依赖性抑制线粒体通透性转换和细胞凋亡介导的。增强 HO-1 或其产物 CO 可能代表改善 HF 的一种新的治疗策略。
