In vivo Bioimaging as a Novel Strategy to Detect Doxorubicin-Induced Damage to Gonadal Blood Vessels

INTRODUCTION: Chemotherapy may induce deleterious effects in normal tissues, leading to organ damage. Direct vascular injury is the least characterized side effect. Our aim was to establish a real-time, in vivo molecular imaging platform for evaluating the potential vascular toxicity of doxorubicin in mice. METHODS: Mice gonads served as reference organs. Mouse ovarian or testicular blood volume and femoral arterial blood flow were measured in real-time during and after doxorubicin (8 mg/kg intravenously) or paclitaxel (1.2 mg/kg) administration. Ovarian blood volume was imaged by ultrasound biomicroscopy (Vevo2100) with microbubbles as a contrast agent whereas testicular blood volume and blood flow as well as femoral arterial blood flow was imaged by pulse wave Doppler ultrasound. Visualization of ovarian and femoral microvasculature was obtained by fluorescence optical imaging system, equipped with a confocal fiber microscope (Cell-viZio). RESULTS: Using microbubbles as a contrast agent revealed a 33% (P<0.01) decrease in ovarian blood volume already 3 minutes after doxorubicin injection. Doppler ultrasound depicted the same phenomenon in testicular blood volume and blood flow. The femoral arterial blood flow was impaired in the same fashion. Cell-viZio imaging depicted a pattern of vessels' injury at around the same time after doxorubicin injection: the wall of the blood vessels became irregular and the fluorescence signal displayed in the small vessels was gradually diminished. Paclitaxel had no vascular effect. CONCLUSION: We have established a platform of innovative high-resolution molecular imaging, suitable for in vivo imaging of vessels' characteristics, arterial blood flow and organs blood volume that enable prolonged real-time detection of chemotherapy-induced effects in the same individuals. The acute reduction in gonadal and femoral blood flow and the impairment of the blood vessels wall may represent an acute universal doxorubicin-related vascular toxicity, an initial event in organ injury

Effect of Dexrazoxane and Amifostine on the Vertebral Bone Quality of Doxorubicin Treated Male Rats

Doxorubicin (DOX) is widely used in combination cocktails for treatment of childhood hematological cancers and solid tumors. A major factor limiting DOX usage is DOX-induced cardiotoxicity. However, it is not known whether protectants like dexrazoxane (DXR) and amifostine (AMF) can prevent DOX-mediated bone damage. The present study investigated whether administration of AMF alone or in combination with DXR would prevent any DOX-mediated bone damage. Male rat pups were treated with DOX, DXR, AMF, and their combinations. On neonate day 38, the bone mineral density (BMD), bone mineral content (BMC) and the micro-architecture of the lumbar vertebrae were analyzed. We have shown that when male rats are treated with DOX, DXR, DOX+DXR, AMF, DOX+AMF or DOX+DXR+AMF, there is a decrease in lumbar vertebral BMD (p<0.05). Furthermore, the relative bone volume (BV/TV) was decreased by DXR, DOX+DXR, and DOX+AMF treatments. Interestingly, DOX+AMF significantly increased BV/TV when compared to DXR treatment (p<0.04). The trabecular number (Tb.N) decreased with DXR and DOX+DXR and increased with DOX+AMF treatments. This information will be useful in designing better cancer combination therapies that do not lead to vertebrae deterioration

MicroRNA Involvement in Immune Activation During Heart Failure

Heart failure is one of the common end stages of cardiovascular diseases, the leading cause of death in developed countries. Molecular mechanisms underlying the development of heart failure remain elusive but there is a consistent observation of chronic immune activation and aberrant microRNA (miRNA) expression that is present in failing hearts. This review will focus on the interplay between the immune system and miRNAs as factors that play a role during the development of heart failure. Several studies have shown that heart failure patients can be characterized by a sustained innate immune activation. The role of inflammatory signaling is discussed and TLR4 signaling, IL-1β, TNFα and IL-6 expression appears to coincide with the development of heart failure. Furthermore, we describe the implication of the renin angiotensin aldosteron system in immunity and heart failure. In the past decade microRNAs (miRNAs), small non-coding RNAs that translationally repress protein synthesis by binding to partially complementary sequences of mRNA, have come to light as important regulators of several kinds of cardiovascular diseases including cardiac hypertrophy and heart failure. The involvement of differentially expressed miRNAs in the inflammation that occurs during the development of heart failure is still subject of investigation. Here, we summarize and comment on the first studies in this field and hypothesize on the putative involvement of certain miRNAs in heart failure. MicroRNAs have been shown to be critical regulators of cardiac function and inflammation. Future research will have to point out if dampening the immune response, and the miRNAs associated with it, during the development of heart failure is a therapeutically plausible route to follow