The heart is especially susceptible to the disruption of mitochondrial energy production. Mitochondrial reactive oxygen species are involved in cell AB1010 signaling, but are also potential mediators of oxidative stress. Oxidative stress mediated by activation of the ANGII type-1 receptor plays a crucial role in the progression of cardiovascular diseases. Results from this study will help us elucidate the role played by TNF in inducing oxidative stress by examining the superoxide producing machinery in the heart, and its contribution to cardiac dysfunction. In this context, the purpose of this study was to investigate whether an AT-1R blocker could attenuate the functional and structural changes that occur in cardiac mitochondria upon TNF induction. Identifying the links between TNF, ANGII, and oxidative stress at the mitochondrial level in contributing to cardiac damage may lead to a better understanding of the progression of cardiovascular disease and, ultimately, lead to new and effective treatment strategies. This assertion is supported by several observations. Increased superoxide production, induced by TNF interacting with ANGII, contributes to mitochondrial dysfunction by depleting mitochondrial genes and proteins and decreasing respiratory complex activity, thereby influencing ATP synthesis and ultimately resulting in cardiac dysfunction. Administration of the ANGII type 1 receptor antagonist losartan, to TNF-treated animals attenuates TNF-induced oxidative stress by modulating free radical production and increasing mitochondrial gene expression, which leads to a normalization of both mitochondrial complex activity and ATP synthesis, and thereby prevents cardiac dysfunction. Our echocardiographic findings suggest that TNF decreases FS% and increases Tei index, both of which are indicative of diastolic dysfunction. We also observed increases in left ventricular diastolic and systolic dimensions, which indicate decreased left ventricular contractile function. Treatment with LOS improved left ventricular contractile function in our study; this could be due to reductions in cytokines and oxidative stress and possible increases in mitochondrial biogenesis gene expression and respiratory chain function. This is supported by our observation that LOS treatment decreased free radical generation both in the cytosol and mitochondria. Mitochondrial dysfunction may play an important pathogenic role in the progression of cardiac dysfunction. In the present study, we report markedly reduced LV tissue levels of specific mitochondrial enzyme activities for respiratory complexes I, II and III, enzymes critical to the generation of ATP. Furthermore, the reduced myocardial complex I,II and complex III levels correlated with the increased LV tissue TNF-a protein levels, suggesting an association between increased TNF-a and mitochondrial dysfunction. In the diabetic rat heart, mitochondrial dysfunction was found to accompany diastolic dysfunction. Further, TNF blockade in dogs with heart failure leads to a restoration of mitochondrial respiratory function in the left ventricle. These observations, paired with our current observations, support a role for decreased mitochondrial bioenergetic function in contributing to diastolic dysfunction. The roles of TNF and ANGII as potent inducers of oxidative stress in a number of cell types, including cardiac myocytes, are well established.