Protective role of chaperone-mediated autophagy against atherosclerosis

Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression

Development of new injectable bulking agents:Biocompatibility of radiopaque polymeric microspheres studies in a mouse model

Radiopaque polymeric microspheres have a potential as new bulking agents for treatment of stress urinary incontinence (SUI). The advantage over existing bulking agents ties in their X-ray visibility in situ; other polymeric bulking agents (e.g., PTFE or silicone rubbers) are practically radiolucent (i.e., incapable of absorbing X-radiation). Radiopacity is useful in practice because of the high spatial accuracy of X-ray imaging. For instance, X-ray fluoroscopy can be used to assess possible migration of the bulking agent over time or to provide guidance in cases in which a second injection of a bulking agent is necessary (repeated treatment of SUI). Biocompatibility of injected radiopaque microspheres was investigated in vivo by using the mouse as a model. Microspheres were injected subcutaneously (9 animals) or intramuscularly (9 animals), and follow-up was 8 days or 3 months. X-ray fluoroscopy gave clear images of the miscrospheres as an ensemble, and it was found that no migration occurred during 3 months. Histopathology confirmed that all microspheres stayed close to the site of the injection. The microspheres appeared to be well tolerated; only a few giant cells, manifesting a mild inflammatory reaction, were encountered. At 3 months, cappillary blood vessels were observed throughout the microsphere beds, and macrophages and fibroblast cells were seen in between the microspheres. This is encouraging with respect to the intended application, although it must be acknowledged that the data refer merely to a mouse model. Further experiments with larger, more representative models (rabbit and goat) are in progress. &amp;COPY; 2005 Wiley Periodicals, Inc.</p

Preliminary evaluation of new intrinsically radiopaque hydrogels for replacing the nucleus pulposus

Treatment of early degenerative disc disease can, in some cases, be accomplished through implantation of a synthetic prosthesis for the nucleus pulposus. This treatment is attractive, since the annulus fibrosus-as well as the function of the disc-is preserved. This study reports on two new synthetic hydrogels which were specifically designed as fully radiopaque prosthetic nucleus biomaterials. Moreover, the new materials were engineered in such a way that they swell in situ (i.e., after implantation) to such an extent that they will fill the entire nucleus cavity. We describe: (i) assessment of the biocompatibility of the new biomaterials in an in vivo animal model, (ii) implantation of the new prosthesis in an ex vivo animal model (porcine spine), followed by (iii) assessment of the visibility of the entire nucleus prosthesis through both CT and MRI. The results further substantiate the idea that the concept of implantation of a prosthesis for the nucleus pulposus can benefit from contemporary insights and developments of novel synthetic biomaterials with intrinsic radiopacity

Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis

Inhibition of CD40-CD40L interactions results in a reduction of innate regulatory T cells (Tregs) in CD40(-/-) mice and induces a stable plaque phenotype in atherosclerosis-prone mouse strains. Here we investigated the effects of leukocyte CD40L on the Treg population and on atherosclerosis. LDLR-/- mice were reconstituted with wild-type or CD40L(-/-) bone marrow (BM). These BM chimeras were analysed by flowcytometry for the presence of innate Tregs (CD45RB(low) CD25(+) CD4) in lymphoid organs and peripheral blood. As in CD40(-/-) mice, the CD45RB(high) :CD45RB(low) CD4 T cell ratio significantly increased and the CD25(+) CD4+ subpopulation significantly decreased in LDLR-/- mice receiving CD40L(-/-) BM compared to LDLR-/- mice receiving wild-type BM. However, atherosclerotic plaque progression and plaque phenotype did not change in LDLR-/- mice reconstituted with CD40L(-/-) BM. In conclusion, the present study shows that CD40-CD40L interactions on leukocytes are essential for the size of the CD45RB(low) CD25(+) CD4 Treg subpopulation. Nevertheless, CD40L deficiency on hemopoietic cells did not affect atherosclerosis, implying that CD40L expressing leukocytes alone are not responsible for the stable plaque phenotype observed after total CD40L blockade. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Myeloid I kappa B alpha Deficiency Promotes Atherogenesis by Enhancing Leukocyte Recruitment to the Plaques

Activation of the transcription factor NF-kappa B appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-kappa B inhibitor I kappa B alpha in atherosclerosis. Myeloid-specific deletion of I kappa B alpha results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that I kappa B alpha-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that I kappa B alpha(del) mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in I kappa B alpha(del) mice more leukocytes are attracted to the plaques. In conclusion, we show that I kappa B alpha deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques

Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice

Diabetes mellitus: pathophysiological changes and therap