These results suggest that attenuation of early-phase cardiac cell death by MT results in a significant prevention of the development of diabetic cardiomyopathy. This process is mediated by MT suppression of mitochondrial oxidative stress.

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.

Background. Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and promote immune activation and left ventricular (LV) remodeling. Methods. Adult male wild-type (WT) C57BL/6 mice, Foxp3-diptheria toxin receptor(DTR) transgenic mice, and tumor necrosis factor(TNF)α receptor-1(TNFR1)−/− mice underwent non-reperfused myocardial infarction (MI) to induce HF, or sham operation. LV remodeling was assessed by echocardiography, and histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays. Results. As compared with WT sham mice, CD4+Foxp3+ Tregs in WT HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after MI, beyond the early phase of wound healing, and exhibited pro-inflammatory Th1-type features with interferon-γ, TNFα, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated anti-angiogenic and pro-fibrotic properties. Selective Treg ablation in Foxp3-DTR mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T-cells and systemic inflammation, and enhancing tissue neovascularization. Importantly, Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis, and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a CCL5/CCR5-dependent manner. Anti-CD25-mediated Treg depletion in WT mice imparted similar benefits on LV remodeling, CACs, and tissue neovascularization. Conclusions. Pro-inflammatory and anti-angiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.