Showing papers by "Translational Research Institute published in 2007"

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Abstract: Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure

Sunitinib, sorafenib and mTOR inhibitors in renal cancer.

Abstract: Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC.

Synchrotron Radiation Coronary Microangiography for Morphometric and Physiological Evaluation of Myocardial Neovascularization Induced by Endothelial Progenitor Cell Transplantation

Abstract: Background— Therapeutic effect of stem cell transplantation (SCTx) for myocardial neovascularization has been evaluated by histological capillary density in small animals. However, it has been technically difficult to obtain imaging evidence of collateral formation by conventional angiography. Methods and Results— Peripheral blood CD34+ and CD34− cells were isolated from patients with critical limb ischemia. PBS, CD34− cells, or CD34+ cells were intramyocardially transplanted after ligating LAD of nude rats. Coronary angiography of ex vivo beating hearts 5 and 28 days after the treatment was performed using the third generation synchrotron radiation microangiography (SRM), which has potential to visualize vessels as small as 20 μm in diameter. The SRM was performed pre and post sodium nitroprusside (SNP) to examine vascular physiology at each time point. Diameter of most collateral vessels was 20 to 120 μm, apparently invisible size in conventional angiography. Rentrop scores at day 28 pre and post SNP were significantly greater in CD34+ cell group than other groups ( P <0.01). To quantify the extent of collateral formation, angiographic microvessel density (AMVD) in the occluded LAD area was analyzed. AMVD on day 28 post SNP, not pre SNP, was significantly augmented in CD34+ cell group than other groups ( P <0.05). AMVD post SNP closely correlated with histological capillary density ( R =0.82, P <0.0001). Conclusions— The SRM, capable of visualizing microvessels, may be useful for morphometric and physiological evaluation of coronary collateral formation by SCTx. The novel imaging system may be an essential tool in future preclinical/translational research of stem cell biology.