Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKß-AMPK-dependent regulation of autophagy.

Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a variety of biological processes including obesity. However, the precise mechanism of action behind obesity-induced changes in autophagy still remains elusive. This study was designed to examine the role of the antioxidant catalase in high fat diet-induced changes in cardiac geometry and function as well as the underlying mechanism of action involved with a focus on autophagy. Wild-type (WT) and transgenic mice with cardiac overexpression of catalase were fed low or high fat diet for 20 weeks prior to assessment of myocardial geometry and function. High fat diet intake triggered obesity, hyperinsulinemia, and hypertriglyceridemia, the effects of which were unaffected by catalase transgene. Myocardial geometry and function were compromised with fat diet intake as manifested by cardiac hypertrophy, enlarged left ventricular end systolic and diastolic diameters, fractional shortening, cardiomyocyte contractile capacity and intracellular Ca²âº mishandling, the effects of which were ameliorated by catalase. High fat diet intake promoted reactive oxygen species production and suppressed autophagy in the heart, the effects of which were attenuated by catalase. High fat diet intake dampened phosphorylation of inhibitor kappa B kinase ß(IKKß), AMP-activated protein kinase (AMPK) and tuberous sclerosis 2 (TSC2) while promoting phosphorylation of mTOR, the effects of which were ablated by catalase. In vitro study revealed that palmitic acid compromised cardiomyocyte autophagy and contractile function in a manner reminiscent of fat diet intake, the effect of which was significantly alleviated by inhibition of IKKß, activation of AMPK and induction of autophagy. Taken together, our data revealed that the antioxidant catalase counteracts against high fat diet-induced cardiac geometric and functional anomalies possibly via an IKKß-AMPK-dependent restoration of myocardial autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Felodipine inhibits ox-LDL-induced reactive oxygen species production and inflammation in human umbilical vein endothelial cells.

Oxidative stress and inflammation are involved in the pathogenesis of atherosclerosis. Calcium channel blockers (CCBs) inhibit the development of atherosclerosis, although the underlying molecular basis has not been completely elucidated. The present study was designed to investigate the effects of felodipine, a CCB, on inflammation and oxidative stress in human umbilical vein endothelial cells (HUVECs) and to examine the underlying mechanisms of action. Oxidized low­density lipoprotein (ox­LDL) was used to induce an inflammatory response in HUVECs. The effects of felodipine were investigated by measuring the content of nitric oxide (NO) and reactive oxygen species (ROS), the mRNA and protein levels of intercellular adhesion molecule 1 (ICAM­1) and vascular cell adhesion protein 1 (VCAM­1), and the mRNA levels of endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), in addition to the adhesion ability of U937 cells to HUVECs. ROS and NO levels were significantly increased in HUVECs following 24­h treatment with 25 mg/l ox­LDL (P<0.01). The increase in ROS was reversed by treatment with felodipine. In addition, NO levels were increased following treatment with 1 µmol/l felodipine (P<0.05). The mRNA expression of ICAM­1, VCAM­1, eNOS and iNOS was increased (P<0.05). Administration of 0.1 µM felodipine significantly decreased the expression of ICAM­1, VCAM­1, and iNOS (P<0.05). The number of U937 cells adhered to ox­LDL­treated HUVECs was significantly increased compared with control, which was reversed by felodipine (0.1 µM). In conclusion, felodipine was demonstrated to inhibit oxidative stress and inflammatory responses, suggesting that it may be used to treat atherosclerosis.

Prevention of pericardial constriction by transcatheter intrapericardial fibrinolysis with urokinase.

OBJECTIVE: To investigate whether intrapericardial urokinase irrigation along with pericardiocentesis could prevent pericardial constriction in patients with infectious exudative pericarditis. METHODS: A total of 94 patients diagnosed as infectious exudative pericarditis (34 patients with purulent pericarditis and 60 with tuberculous pericarditis, the disease courses of all patients were less than 1 month), 44 males and 50 females, aged from 9 to 66 years (mean 45.4 +/- 14.7 years), were consecutively recruited from 1993 to 2002. All individuals were randomly given either intrapericardial urokinase along with conventional treatment in study group, or conventional treatment alone (including pericardiocentesis and drainage) in control group. The dosage of urokinase ranged from 200000 to 600000 U (mean 320000 +/- 70000 U). The immediate effects were detected by pericardiography with sterilized air and diatrizoate meglumine as contrast media. The long-term investigation depended on the telephonic survey and echocardiographic examination. The duration of following-up ranged from 8 to 120 months (mean 56.8 +/- 29.0 months). RESULTS: Percutaneous intrapericardial urokinase irrigation promoted complete drainage of pericardial effusion, significantly reduced the thickness of pericardium (from 3.1 +/- 1.6 mm to 1.6 +/- 1.0 mm in study group, P < 0.001; from 3.4 +/- 1.6 mm to 3.2 +/- 1.8 mm in control group, P > 0.05, respectively), and alleviated the adhesion. Intrapericardial bleeding related to fibrinolysis was found in 6 of 47 patients with non-blood pericardial effusion and no systemic bleeding and severe puncture-related complication was observed. In follow-up, there was no cardiac death, and pericardial constriction events were observed in 9 (19.1%) of study group and 27 (57.4%) of control group. Cox analysis illustrated that urokinase could significantly reduce the occurrence of pericardial constriction (relative hazard coefficient = 0.185, P < 0.0001). CONCLUSION: The early employment of intrapericardial fibrinolysis with urokinase and pericardiocentesis appears to be safe and effective in preventing the development of pericardial constriction in patients with infectious exudative pericarditis.