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      Dual AAV/IL-10 Plus STAT3 Anti-Inflammatory Gene Delivery Lowers Atherosclerosis in LDLR KO Mice, but without Increased Benefit

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          Abstract

          Both IL-10 and STAT3 are in the same signal transduction pathway, with IL-10-bound IL10 receptor (R) acting through STAT3 for anti-inflammatory effect. To investigate possible therapeutic synergism, we delivered both full-length wild-type human (h) STAT3 and hIL-10 genes by separate adenoassociated virus type 8 (AAV8) tail vein injection into LDLR KO on HCD. Compared to control Neo gene-treated animals, individual hSTAT3 and hIL-10 delivery resulted in significant reduction in atherogenesis, as determined by larger aortic lumen size, thinner aortic wall thickness, and lower blood velocity (all statistically significant). However, dual hSTAT3/hIL-10 delivery offered no improvement in therapeutic effect. Plasma cholesterol levels in dual hSTAT3/hIL-10-treated animals were statistically higher compared to hIL-10 alone. While no advantage was seen in this case, we consider that the dual gene approach has intrinsic merit, but properly chosen partnered genes must be used.

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          Cancer genes and the pathways they control.

          Bert Vogelstein, Kenneth W. Kinzler (2004)
          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells.

            P Hermonat, N Muzyczka (1984)
            Adeno-associated virus (AAV) is a human DNA virus that has a broad host range and can be grown both as an integrated provirus and as a lytic genome. These properties suggested that AAV may be useful as a mammalian transduction vector. To test this possibility, we have isolated a recombinant AAV viral stock in which the neomycin resistance gene was substituted for the AAV capsid genes. Using this recombinant stock, we have demonstrated that AAV can be used to transduce foreign DNA into human and murine tissue culture cells. In addition, we have demonstrated that, if the transductants are superinfected with a helper virus (adenovirus), the recombinant AAV genome is rescued from the proviral state and amplified to high copy number. These unique features of AAV vectors suggest that they may have a broad utility in the study of biological problems. Because AAV, itself, is nonpathogenic in both humans and animals, these vectors also may be useful for the purpose of gene therapy.
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              Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose.

              Sean Shaw, Jie Tang, B Marrero … (2002)
              Both high glucose (HG) and angiotensin II (Ang II) causes glomerular mesangial cell (GMC) growth and increased synthesis of matrix proteins like collagen IV contributing to diabetic nephropathy. We have recently found that exposure of vascular smooth muscle cells to HG augments the Ang II activation of the growth promoting JAK/STAT pathway. We hypothesized that Ang II activation of the JAK/STAT pathway is altered by HG in GMC, and that this pathway might be linked to the Ang II-induced growth and overproduction of collagen IV in GMC in HG conditions. GMC were cultured under normal glucose (NG; 5.5 mmol/L) and HG (25 mmol/L) for 48 hours and stimulated with Ang II (0.1 micromol/L) for various times. GMC lysate was then immunoprecipitated and/or immunoblotted with SHP-1, SHP-2 and phosphospecific JAK2 and STAT antibodies. The HG and Ang II induced growth and collagen IV synthesis studies were performed in GMC transfected with JAK2 antisense or JAK2 sense. GMC growth was monitored via [3H]-thymidine incorporation, and collagen IV synthesis via ELISA. We found that Ang II-induced JAK2, STAT1, STAT3, STAT5A/B and SHP-2 phosphorylations were enhanced by HG, whereas that of SHP-1 was reduced. Ang II-induced growth and collagen IV synthesis also were increased under HG conditions. Transfection of GMC with JAK2 antisense oligonucleotides blocked the Ang II-induced growth and collagen IV synthesis in both NG and HG conditions. These results provide evidence that activation of the JAK/STAT pathway by HG or/and Ang II may be of importance in the increased GMC cell growth and collagen IV synthesis that is seen in diabetic nephropathy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Vasc Med
                Journal ID (publisher-id): IJVM
                Title: International Journal of Vascular Medicine
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-2824
                ISSN (Electronic): 2090-2832
                Publication date (Print): 2012
                Publication date (Electronic): 11 September 2011
                Volume: 2012
                Electronic Location Identifier: 524235
                Affiliations
                1Central Arkansas Veterans Healthcare System, 111J, 4300 West 7th Street, Little Rock, AR 72205, USA
                2Research of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR 72205, USA
                3Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, GA 30033, USA
                Author notes
                *Paul L. Hermonat: plhermonat@ 123456uams.edu

                Academic Editor: Manuel Castro Cabezas

                Article
                DOI: 10.1155/2012/524235
                PMC ID: 3170890
                PubMed ID: 21915378
                SO-VID: 1f724b92-99fc-4c93-b1e6-1d379788ea45
                Copyright © Copyright © 2012 Maohua Cao et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 25 April 2011
                Date accepted : 20 June 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Cardiovascular Medicine
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine

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