Increased ROS production could eventually lead to SM 324405 impaired mitochondrial function which ultimately could be associated with decreased DYm, and ROS production in the setting of high matrix could lead to opening of a non-specific pore in the mitochondrial membrane known as the mitochondrial permeability transition pore. Increased ROS production could have other consequences as well, including reduced contractile function, as has been observed with postischemic stunning. In fact, like our miR-181c overexpressor model, the role of ROS and Ca2+ in the pathogenesis of myocardial IDE 2 stunning is well documented ; including mitochondrial matrix overload. Our data suggest that complex IV remodeling affects more than just the subunits that are products of the mitochondrial genome and subject to direct regulation by miR-181c within the mitochondrial matrix. There are also changes to peripheral complex IV subunits that are products of the nuclear genome such as COX VIIa, but not to all of the subunits derived from the nuclear genome such as COX 5A and COX 5B. The loss of COX VIIa protein over time, as well as mt-COX2, may be related to increased degradation. A role for LON-mediated degradation of COX subunits in regulation of complex IV subunit composition has been reported previously. Taken together, the results demonstrate that chronic overexpression of miR-181c has a role in heart failure by targeting the mitochondrial gene, mt-COX1, which ultimately leads to dysfunctional complex IV, altered mitochondrial metabolism, and ROS generation. We have also identified an underlying mechanism by which complex IV inhibition can activate ROS production in the mitochondria, by increasing matrix, which activates mitochondrial dehydrogenases. Our study used a novel systemic miRNA delivery system, using cationic nanovectors, in the heart. This technology may lead to innovative new therapeutic interventions for heart disease. Vitamin E exists as eight distinct isomers, all of which have strong anticarcinogenic properties, including antioxidant and apoptotic characteristics. Additionally, many epidemiologic studies support the use of vitamin E as a chemopreventive agent. The isomer a-tocopherol succinate has been recognized as an effective form of vitamin E for use as an adjuvant in cancer therapy for its ability to inhibit proliferation and induce apoptosis in cancer cells. These properties of vitamin E may make it an ideal supplement to standard cancer treatments such as chemotherapy as well as immunotherapies that modify the tumor microenvironment.