Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer

Circulation
C EmanueliP Madeddu

Abstract

Angiogenesis gene therapy with human tissue kallikrein (hTK) has shown promise for ischemic disease. The present study was undertaken to (1) assess an optimal gene transfer modality, (2) clarify hTK angiogenic pathways, and (3) discount possible side effects. The hTK gene was transferred to murine adductors by increasing doses of an adenovirus (Ad.hTK). Heterologous protein production was evaluated by ELISA and immunohistochemistry. Structural and functional characteristics of hTK-induced neovascularization were assessed. Muscular endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF)-A mRNA and protein content were evaluated by real-time polymerase chain reaction and Western blotting. The ability of hTK to phosphorylate-activate Akt/protein kinase B (Akt-B) and VEGF receptor 2 (VEGF-R2) was also determined. Implication of the aforementioned mechanisms in Ad.hTK-induced neovascularization was challenged by blocking Akt-B with a dominant-negative Akt construct; NOS with N(G)-nitro-L-arginine methyl ester; and VEGF-A with neutralizing antibody, VEGF-R2 antagonist, or Ad carrying soluble VEGF-R1 gene. We found that 10(7) PFU Ad.hTK led to peak increases in capillary and arteriole density. Newly deve...Continue Reading

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Citations

Mar 29, 2007·Nature Clinical Practice. Nephrology·Paolo MadedduSamir El-Dahr
Feb 19, 2008·Cardiovascular Research·Gaia SpinettiPaolo Madeddu
Oct 7, 2008·Cardiovascular Research·Anton J G Horrevoets
Dec 13, 2005·Current Opinion in Nephrology and Hypertension·Frank SpillmannCarsten Tschöpe
Oct 14, 2005·Kidney International·Bernardo Rodríguez-IturbeNosratola D Vaziri
Jan 24, 2009·Arteriosclerosis, Thrombosis, and Vascular Biology·Oliver A StonePaolo Madeddu
Apr 3, 2010·Arteriosclerosis, Thrombosis, and Vascular Biology·Brunella CristofaroCostanza Emanueli
Dec 18, 2010·Circulation Research·Gaia SpinettiPaolo Madeddu
Jan 5, 2013·Circulation Research·Betty DescampsCostanza Emanueli
Mar 20, 2009·Expert Review of Cardiovascular Therapy·Nicolle Kränkel, Paolo Madeddu
Oct 26, 2012·Expert Opinion on Drug Discovery·Eric T WhalleyKanti D Bhoola
Dec 29, 2009·Neuropeptides·Konstantinos SavvatisCarsten Tschöpe
Sep 30, 2006·Vascular Pharmacology·Costanza Emanueli, Paolo Madeddu
Nov 29, 2005·The International Journal of Biochemistry & Cell Biology·Malgorzata MilkiewiczTara L Haas
May 11, 2005·Trends in Molecular Medicine·Costanza Emanueli, Paolo Madeddu
Mar 22, 2005·Experimental Physiology·Paolo Madeddu
Sep 23, 2010·British Journal of Cancer·P DominekP Madeddu
Jan 5, 2007·Journal of the American Society of Nephrology : JASN·Takahiko NakagawaByron Croker
Nov 15, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thomas KryzaNathalie Heuzé-Vourc'h
Sep 13, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Gian Paolo FadiniPaolo Madeddu

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