| Heart failure is a progressive disease and a better understanding of the factors involved in its progression is needed to develop effective and specific therapies. Oxidative stress as well as inflammation is considered to be important factors in the pathogenesis of heart failure subsequent to myocardial infarction. It is now well documented that endogenous TNF-alpha play a central role in initiating and sustaining the inflammatory cytokine cascade. TNF-alpha is overexpressed in left ventricular dysfunction, cardiomyopathy, pulmonary edema and heart failure and is known to increase oxidative stress. In contrast, another cytokine, interleukin-10 (IL-10) is anti-inflammatory that down regulates the expression of several pro-inflammatory cytokines, including that of TNF-alpha. IL-10 has been shown to antagonize some of the deleterious effects of TNF-alpha. IL-10 is also known to inhibit the generation of reactive oxygen species (ROS). Considering the anti-TNF-alpha effects of IL-10, it is possible that the suggested role of TNF-alpha in the pathogenesis of heart failure may in fact be accentuated by a fall in the levels of IL-10.; In this study, I tested the possibility that (i) A decrease in the levels of IL-10 along with an increase in TNF-alpha is involved in the pathogenesis of congestive heart failure subsequent to coronary artery ligation in rats. (ii) An imbalance of these two cytokines in the pathogenesis of congestive heart failure leads to increased oxidative stress thus causing cardiac dysfunction, due to their disparate effects.; To test this hypothesis, congestive heart failure was induced in rats by occluding the left descending coronary artery. The cardiac function at 1, 4, 8 and 16 weeks post myocardial infarction (PMI) was assessed using indwelling catheter with a pressure sensitive tip transducer and as well as by echocardiography. RT-PCR was performed on frozen tissue samples to determine the mRNA levels of TNF-alpha and IL-10 and ELISA was performed to examine changes in the membrane bound and soluble protein fractions of these cytokines during the progression of heart failure. Losartan treatment (2 mg/ml in drinking water, daily) was given to modify the cardiac function to examine the validity of the relationship between these cytokine changes and cardiac function. In in vitro studies, isolated adult cardiac myocytes were used to test the interplay of these cytokines in regards to oxidative stress and cardiac cell injury. Myocytes were exposed for 4 hours to different concentrations of TNF-alpha and IL-10 (1-20 ng/ml) alone or in combination. Cell lysates were then analyzed for protein levels and mRNA levels for Copper/zinc superoxide dismutase (Cu/Zn-SOD), Manganese superoxide dismutase (MnSOD), Catalase (Cat) and Glutathione peroxidase (GSHPx). Oxidative stress was measured by quantifying the generation of reactive oxygen species by redox-sensitive fluorescence dye (H2DCFDA) as well as by the study of lipid peroxidation. Creatine kinase (CK) release in the culture medium was assayed to assess cell injury. As a positive control, cardiac myocytes were exposed to H2O2 to induce oxidative stress. All these parameters were also examined in these H2O2 exposed cardiac myocytes.; Cardiac function deteriorated with post ligation duration in PMI groups, with a severe failure seen at 16 W PMI. Echocardiographic studies revealed differences between sham and respective PMI groups as early as 4 weeks after the coronary ligation. In the PMI groups fractional shortening, ejection fraction, left ventricular peak systolic pressure and (+)dP/dt and (-)dP/dt decreased significantly at all time points starting with 4W PMI. These changes were accompanied by an increase in left ventricular end diastolic pressure.; TNF-alpha protein fractions, both membrane bound and soluble, were significantly increased in 1 and 4W PMI groups and its levels were unchanged in 8 and 16 W PMI groups vs control groups. TNF-alpha mRNA was significantl... |
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