This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.
Modulating angiogenesis is an attractive goal because many pathological conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, we designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17-25. NMR conformation analysis of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the ␣-helix region of VEGF, VEGF15, is unstructured. Biological assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biological activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biological response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17-25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biological properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and molecules mimicking it could be attractive for therapeutic and diagnostic applications.helical peptides ͉ peptide design ͉ VEGF ͉ angiogenesis ͉ NMR spectroscopy
Background
Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure (HF). The chronic adrenergic stimulation that accompanies HF is a signaling abnormality that leads to the up-regulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part due to uncoupling of the β-adrenergic receptor (βAR) system. In this study we explored the possibility that enhanced GRK2 expression and activity, as seen during HF, can negatively affect cardiac metabolism as part of its pathogenic profile.
Methods and Results
Positron Emission Tomography (PET) studies revealed that transgenic mice with cardiac-specific overexpression of GRK2 negatively impacted cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes HF development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 (IRS1) in cardiomyocytes causing insulin-dependent negative signaling feedback including inhibition of membrane translocation of the glucose transporter, GLUT4. This identifies IRS1 as a novel non-receptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents post-ischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of HF.
Conclusions
Our data provide novel insight into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through βARs and metabolism through the insulin receptor.
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