Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heart failure both in human disease and preclinical models. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heart failure, as suggested by clinical as well as experimental evidence. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. 4Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, GermanyĮndothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology.3Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.2Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.1Center for Cardiology, Cardiology I, Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.The results obtained will generate important intellectual property value and will constitute the basis for further development towards the generation of novel therapies against heart failure.Rajinikanth Gogiraju 1,2,3,4, Magdalena L. APPROACH: We will identify direct downstream targets of the miR-106b~25 cluster during hypertrophy, by performing Ago2-Immunoprecipitation and by treating neonatal cardiomyocytes with precursors of miR-25, miR-93 and miR-106b, followed by next generation sequencing (Objective 1) We aim to reverse pathological cardiac remodeling and prevent heart failure by delivery of recombinant adeno-associated virus (rAAV9)- miR-106b~25 in mice (Objective 2). AIM: To define the functional implication of the miR-106b~25 cluster in pathological cardiac hypertrophy and to exploit this information towards the development of novel therapeutic approaches. Following bioinformatics screens for potential direct downstream targets of the miR-25~106b cluster, we identified a series of transcription factors, which might play a role in pathological cardiac remodeling. Our pilot-data show that expression of the miR-106b~25 cluster decreases during pathological hypertrophy in mice and that virus-mediated overexpression of this cluster prevents phenylephrine-induced hypertrophic remodeling. In particular, recent data demonstrate that dysregulated microRNAs (miRs) are associated with heart failure, and that selective modulation of miRs can provide therapeutic benefits. There is now clear indication that, besides a few known transcriptional regulators, multiple, still poorly understood cardiac factors are involved in hypertrophy understanding this complexity is expected to pave to the way to innovative therapies. In particular, sustained pathological hypertrophy, a major predictor of this condition, is a complex process, which involves transcriptional and posttranscriptional regulation of the cardiac genome. BACKGROUND: There is a tremendous need to develop novel therapies for heart failure.
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