Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity

Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EETs). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized transgenic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 ± 2%, CYP2J2 Tr 47 ± 1%). WT mice also had larger increases in β-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 ± 0.25 vs. 1.6 ± 0.50 ng·min−1·100 μg protein−1). In vitro data from H9c2 cells demonstrated that EETs attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity

The Immunosuppressive Activity of Polymeric Micellar Formulation of Cyclosporine A: In Vitro and In Vivo Studies

We have previously developed micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and delivery of cyclosporine A (CsA). These micelles were able to reduce the renal uptake and nephrotoxicity of CsA. The purpose of the current study was to test the efficacy of polymeric micellar formulation of CsA (PM-CsA) in suppressing immune responses by either T cells or dendritic cells (DCs). The performance of PM-CsA was compared to that of the commercially available formulation of CsA (Sandimmune®). Our results demonstrate that PM-CsA could exert a potent immunosuppressive effect similar to that of Sandimmune® both in vitro and in vivo. Both formulations inhibited phenotypic maturation of DCs and impaired their allostimulatory capacity. Furthermore, both PM-CsA and Sandimmune® have shown similar dose-dependent inhibition of in vitro T cell proliferative responses. A similar pattern was observed in the in vivo study, where T cells isolated from both PM-CsA-treated and Sandimmune®-treated mice have shown impairment in their proliferative response and IFN-γ production at similar levels. These results highlight the potential of polymeric micelles to serve as efficient vehicles for the delivery of CsA