Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several drugs targeting the pathogenesis of aortic aneurysm have shown efficacy in model systems but not in clinical trials, potentially owing to the lack of targeted drug delivery. Here, we designed a novel drug delivery system using nanoparticles to target the disrupted aortic aneurysm micro-structure. We generated poly(ethylene glycol)-shelled nanoparticles incorporating rapamycin that exhibited uniform diameter and long-term stability. When injected intravenously into a rat model in which abdominal aortic aneurysm (AAA) had been induced by infusing elastase, labeled rapamycin nanoparticles specifically accumulated in the AAA. Microscopic analysis revealed that rapamycin nanoparticles were mainly distributed in the media and adventitia where the wall structures were damaged. Co-localization of rapamycin nanoparticles with macrophages was also noted. Rapamycin nanoparticles injected during the process of AAA formation evinced significant suppression of AAA formation and mural inflammation at 7 days after elastase infusion, as compared with rapamycin treatment alone. Correspondingly, the activities of matrix metalloproteinases and the expression of inflammatory cytokines were significantly suppressed by rapamycin nanoparticle treatment. Our findings suggest that the nanoparticle-based delivery system achieves specific delivery of rapamycin to the rat AAA and might contribute to establishing a drug therapy approach targeting aortic aneurysm.
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PMID:Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats. 2733 52

The development of effective pharmacological treatment of abdominal aortic aneurysm (AAA) potentially offers great benefit to patients with preaneurysmal aortic dilation by slowing the expansion of aneurysms and reducing the need for surgery. To date, therapeutic targets for slowing aortic dilation have had low efficacy. Thus, in this study, we aim to elucidate possible mechanisms driving aneurysm progression to identify potential targets for pharmacological intervention. We demonstrate that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells (SMCs), which contributes to murine AAA. Rapamycin, a typical mTOR pathway inhibitor, dramatically limits the expansion of the abdominal aorta following intraluminal elastase perfusion. Furthermore, reduction of aortic diameter is achieved by inhibition of the mTOR pathway, which preserves and/or restores the contractile phenotype of SMCs and downregulates macrophage infiltration, matrix metalloproteinase expression, and inflammatory cytokine production. Taken together, these results highlight the important role of the mTOR cascade in aneurysm progression and the potential application of rapamycin as a therapeutic candidate for AAA.NEW & NOTEWORTHY This study provides novel observations that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells and contributes to mouse abdominal aortic aneurysm (AAA) and that rapamycin protects against aneurysm development. Our data highlight the importance of preservation and/or restoration of the smooth muscle cell contractile phenotype and reduction of inflammation by mTOR inhibition in AAA.
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PMID:Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion. 2821 5

Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.
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PMID:Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery. 2857 52