title: Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2 S availability.
abstract: OBJECTIVE
  Hydrogen sulfide (H2 S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2 S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2 S availability.
  
  
  METHODS
  HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments.
  
  
  RESULTS
  Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2 S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2 S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP ) channels, the molecular target that mediates part of the vascular functions of H2 S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2 S response to H2 S and KATP activation.
  
  
  CONCLUSIONS
  Zofenoprilat induced a constant production of H2 S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2 S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced.
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: E
authors: E
authors: Terzuoli
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: M
authors: M
authors: Monti
authors: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
authors: V
authors: V
authors: Vellecco
authors: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
authors: M
authors: M
authors: Bucci
authors: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
authors: G
authors: G
authors: Cirino
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: M
authors: M
authors: Ziche
authors: Department of Life Sciences, University of Siena, Siena, Italy.
authors: L
authors: L
authors: Morbidelli
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006862:Hydrogen Sulfide / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D000806:Angiotensin-Converting Enzyme Inhibitors; D054086:KATP Channels; D016222:Fibroblast Growth Factor 2; C065520:zofenoprilate; D002216:Captopril; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
references: Am J Respir Cell Mol Biol. 2012 Oct;47(4):491-6
references: 22592920
references: J Mol Med (Berl). 2012 Mar;90(3):255-63
references: 22314625
references: Circulation. 2013 Jan 29;127(4):424-34
references: 23357661
references: Antioxid Redox Signal. 2013 May 20;18(15):1906-19
references: 23176571
references: Biochem Genet. 2013 Aug;51(7-8):503-13
references: 23515848
references: Circ Heart Fail. 2013 Sep 1;6(5):1077-86
references: 23811964
references: Pharmacol Res. 2013 Oct;76:171-81
references: 23965518
references: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references: 24234439
references: PLoS One. 2014;9(1):e84358
references: 24392129
references: Br J Pharmacol. 2013 Dec;170(8):1607-51
references: 24528239
references: Br J Pharmacol. 2013 Dec;170(8):1797-867
references: 24528243
references: Cardiovasc Res. 2014 Apr 1;102(1):138-47
references: 24501330
references: J Pharmacol Exp Ther. 2014 Dec;351(3):500-9
references: 25238748
references: Am J Hypertens. 2002 Oct;15(10 Pt 1):891-5
references: 12372676
references: Nat Med. 2003 Jun;9(6):669-76
references: 12778165
references: Nat Med. 2003 Jun;9(6):685-93
references: 12778167
references: Amino Acids. 2004 Jun;26(3):243-54
references: 15221504
references: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9161-6
references: 22570497
references: EMBO J. 2001 Nov 1;20(21):6008-16
references: 11689441
references: Biochem J. 1982 Aug 15;206(2):267-77
references: 7150244
references: Am J Physiol. 1997 May;272(5 Pt 2):H2507-11
references: 9176323
references: J Int Med Res. 2005 Jan-Feb;33(1):42-54
references: 15651714
references: FASEB J. 2006 Mar;20(3):553-5
references: 16507767
references: FASEB J. 2006 Oct;20(12):2118-20
references: 16912151
references: J Pharmacol Exp Ther. 2006 Nov;319(2):515-22
references: 16868034
references: FASEB J. 2007 Jul;21(9):2162-72
references: 17341678
references: Cardiovasc Res. 2007 Oct 1;76(1):29-40
references: 17631873
references: Nat Rev Drug Discov. 2007 Nov;6(11):917-35
references: 17948022
references: J Cardiovasc Pharmacol. 2009 Oct;54(4):287-97
references: 19620880
references: Sci Signal. 2009;2(96):ra72
references: 19903941
references: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21972-7
references: 19955410
references: J Pharmacol Exp Ther. 2010 Mar;332(3):776-84
references: 19959747
references: J Mol Cell Cardiol. 2010 Apr;48(4):746-56
references: 19913548
references: Br J Pharmacol. 2010 Aug;160(7):1573-6
references: 20649560
references: Br J Pharmacol. 2010 Aug;160(7):1577-9
references: 20649561
references: Biol Pharm Bull. 2010;33(9):1550-4
references: 20823573
references: Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1998-2004
references: 20634473
references: Annu Rev Pharmacol Toxicol. 2011;51:169-87
references: 21210746
references: PLoS One. 2011;6(3):e18076
references: 21464949
references: Amino Acids. 2011 Jun;41(1):113-21
references: 20191298
references: PLoS One. 2011;6(6):e20525
references: 21738579
references: Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13829-34
references: 21808008
references: Br J Pharmacol. 2011 Oct;164(3):853-65
references: 21198548
references: Int J Biol Sci. 2012;8(4):430-41
references: 22419888
references: PLoS One. 2012;7(12):e53319
references: 23285278