title: Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction.
abstract: Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium.
authors.affiliation: Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, Health Center, University of Connecticut, Farmington, Connecticut, USA.
authors.forename: Ram Sudheer
authors.initials: RS
authors.lastname: Adluri
authors.forename: Mahesh
authors.initials: M
authors.lastname: Thirunavukkarasu
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhan
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Dunna
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Akita
authors.forename: Vaithinathan
authors.initials: V
authors.lastname: Selvaraju
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Juan A
authors.initials: JA
authors.lastname: Sanchez
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002908:Chronic Disease; D054477:Glutaredoxins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009841:Oligonucleotides; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020257:Ventricular Remodeling; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D054477:Glutaredoxins; D016328:NF-kappa B; D009841:Oligonucleotides; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt