Cardioprotective and Antiapoptotic Effects of Heme Oxygenase-1 in the Failing Heart

Abstract

Background-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. Methods and Results-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 (PϽ0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46Ϯ8 versus 85Ϯ32 L), mechanical dysfunction (ejection fraction, 65Ϯ9% versus 49Ϯ16%), hypertrophy (LV/tibia length 4.4Ϯ0.4 versus 5.2Ϯ0.6 mg/mm), interstitial fibrosis (11.2Ϯ3.1% versus 18.5Ϯ3.5%), 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 H 2 O 2 -induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis. Conclusions-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.

Inflammatory cell tumor necrosis factor signaling modulates post-infarction left ventricular remodeling.

“…However, when compared to WTc sham, WTc HF animals showed an approximately 40% mortality. This is in line with previously observed mortality rates for C57BLl6 permanent coronary ligation models in both our laboratory and others [63,92]. Interestingly, in postinfarction HF, we found that ablation of either TNF receptor in the inflammatory cell compartment improved survival significantly over WTc HF animals (80% vs. 60%).…”

“…Under Trichrome (for collagen) using standard histologic techniques [63,92]. The degree of tissue fibrosis (blue-green stain) was assessed using Metamorph…”

“…Coronary ligation and experimental protocol. Permanent coronary ligation was performed as previously described [63,92]. Anesthesia was induced in mice with tribromoethanol (0.25 mg/g IP).…”

Induction of Heme Oxygenase-1 by Na+-H+ Exchanger 1 Protein Plays a Crucial Role in Imatinib-resistant Chronic Myeloid Leukemia Cells

“…4, E-G). (25,26); its expression is however obviously up-regulated in different types of cancer, as it is associated with promotion of tumor cell survival (27,28). In this study, we primarily proved that HO-1 was induced by NHE1 activation.…”

Sudden cardiac death in the young: cytokines and pathways

“…HO-1 overexpression inhibits proinflammatory cytokines and chemokines under hypoxia, alleviates cardiomyocyte apoptosis and regulating pathological left ventricular remodeling (23). The anti-inflammatory properties of HO-1 may rely on its ability to degrade heme and generate bilirubin, free iron and CO, and to reverse IL-18-mediated p38a MAPK and nuclear factor-kB activation, phosphatase and tensin homolog (PTEN) induction, Akt suppression and endothelial cell death (24).…”