Doxorubicin (Doxo) is one of multiple anthracycline drugs used to effectively treat various forms of cancer. Unfortunately, Doxo treatment, as a side effect, induces cardiomyopathy and subsequent heart failure. We have previously demonstrated that transplanted embryonic stem (ES) cells and their conditioned medium (CM) modulate the PTEN pathway and reduce apoptosis, fibrosis and hypertrophy in a Doxo induced cardiomyopathy (DIC) model. However, mechanisms of inhibited apoptosis mediated through PTEN pathway are completely unknown. Therefore, we used VO-OHpic (VO), a potent PTEN inhibitor to understand the mechanism of apoptosis as well as its effect on cardiac remodeling in DIC. Animals were divided into three groups; Group 1: Control (Saline), Group 2: Doxo (12 mg/kg, cumulative dose) and Group 3: Doxo+VO (30ug/kg cumulative dose). Animals were studied at one week and eight weeks post-DIC. Mice were subjected to echocardiography to examine cardiac function, sacrificed and hearts were harvested for further analysis. Immunohistochemistry staining revealed a significant (p lt& 0.05) decrease in apoptotic cardiomyocytes in Doxo+VO treated hearts compared with Doxo group. Furthermore, Hematoxylin and Eosin (H&E) and Masson's Trichrome histological stains confirmed reduced hypertrophy and fibrosis in Doxo+VO treated subjects compared to Doxo group. Western Blotting confirmed the reduction of p-PTEN levels and the increase in p-AKT cell survival protein expression in Doxo+VO subjects. In addition, VO-OHpic administration was shown to reduce the number of pro-inflammatory macrophages and increase the number of anti-inflammatory M2 macrophages that may further be involved in reduced apoptosis and fibrosis. Finally, heart function was improved in mice treated with VO compared to Doxo group. Collectively, our data suggests that VO-OHpic treatment reduces apoptosis, cardiac fibrosis and the process is mediated through the PTEN/AKT and inflammatory mechanisms with improved heart function in the DIC heart.
Master of Science (M.S.)
College of Medicine
Molecular Biology & Microbiology
Length of Campus-only Access
Masters Thesis (Open Access)
Johnson, Taylor, "VO-OHpic Treatment Reduces Cardiac Remodeling in Doxorubicin-Induced Cardiomyopathy" (2016). Electronic Theses and Dissertations. 5466.