Background-Tumor necrosis factor-␣ (TNF-␣) and angiotensin II (Ang II) are implicated in the development and further progression of heart failure, which might be, at least in part, mediated by the production of reactive oxygen species (ROS). However, the cause and consequences of this agonist-mediated ROS production in cardiac myocytes have not been well defined. Recently, we demonstrated that increased ROS production was associated with mitochondrial DNA (mtDNA) damage and dysfunction in failing hearts. We thus investigated whether the direct exposure of cardiac myocytes to TNF-␣ and Ang II in vitro could induce mtDNA damage via production of ROS. Methods and Results-TNF-␣ increased ROS production within cultured neonatal rat ventricular myocytes after 1 hour, as assessed by 2Ј,7Ј-dichlorofluorescin diacetate fluorescence microscopy. TNF-␣ also decreased mtDNA copy number by Southern blot analysis in association with complex III activity, which was prevented in the presence of the antioxidant ␣-tocopherol. A direct exposure of myocytes to H 2 O 2 caused a similar decrease in mtDNA copy number. In contrast, Ang II did not affect mtDNA copy number, despite the similar increase in ROS production. TNF-␣-mediated ROS production and a decrease in mtDNA copy number were inhibited by the sphingomyelinase inhibitor D609. Furthermore, N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analogue, increased myocyte ROS production, suggesting that TNF-␣-mediated ROS production and subsequent mtDNA damage were mediated by the sphingomyelin-ceramide signaling pathway. Conclusions-The intimate link between TNF-␣, ROS, and mtDNA damage might play an important role in myocardial remodeling and failure.

The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

Background-Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown. Methods and Results-Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; PϽ0.05) without affecting the infarct size (52Ϯ2% versus 49Ϯ3%; PϭNS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice. Conclusions-Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.

Background-Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI). Methods and Results-We created MI in 12-to 16-week-old, male GSHPx transgenic mice (TGϩMI) and nontransgenic wild-type littermates (WTϩMI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid-reactive substances measured in TGϩMI at 4 weeks were significantly lower than those in WTϩMI. The survival rate during 4 weeks of MI was significantly higher in TGϩMI than in WTϩMI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TGϩMI. LV end-diastolic pressure was increased in WTϩMI and reduced in TGϩMI. Improvement of LV function in TGϩMI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WTϩMI after 3 days but were attenuated in TGϩMI. Conclusions-Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.

Background-Increased expression of monocyte chemoattractant protein-1 (MCP-1) has recently been described in clinical and experimental failing heart. However, its pathophysiological significance in heart failure remains obscure. We thus determined whether MCP-1 is increased in post-myocardial infarction (MI) hearts and its blockade can attenuate the development of left ventricular (LV) remodeling and failure. Methods and Results-Anterior MI was produced in mice by ligating the left coronary artery. After 4 weeks, MI mice exerted LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV. MCP-1 mRNA levels were increased by 40-fold in noninfarcted LV 1 day after ligation, which persisted until 28 days. To block the MCP-1 signals, an N-terminal deletion mutant of the human MCP-1 gene was transfected into the limb skeletal muscle 3 days before and 14 days after ligation. This method improved the survival rate of mice with MI at 4 weeks (61% versus 87%, PϽ0.05) as well as attenuated LV cavity dilatation and contractile dysfunction, interstitial fibrosis, recruitment of macrophages, and myocardial gene expression of tumor necrosis factor-␣ and transforming growth factor-␤ compared with the nontreated MI mice despite the comparable infarct size calculated as percent LV circumference. Conclusions-The