Identification of HIV-1 Tat peptides for future therapeutic angiogenesis.
Therapeutic angiogenesis represents a novel approach to treat critical limb ischemia when revascularization is no more an option. The clinical use of the vascular endothelial growth factor is questioned, because of its side effects. This study was designed to identify and characterize human immunodeficiency virus type 1 (HIV-1) Tat-derived peptides based on their pro-angiogenic properties. A series of Tat-derived peptides were synthesized containing mutations in the basic domain. To minimize side effects Tat peptides were selected exerting no effects on the proteasome and on the viability of human umbilical vein endothelial cells (HUVEC). Tatpep5, 15, and 16 increased the endogenous levels of the pro-angiogenic transcription factors c-Jun and SP-1 as well as the production of the plasminogen activator inhibitor-1 (PAI-1) by HUVEC. A significant induction of endothelial cell invasion was observed upon treatment of HUVEC with Tat peptides. In addition, selected Tat peptides induced tube formation by HUVEC as visualized and quantified in a Matrigel matrix. Our data demonstrate that the selected Tat peptides fulfill essential criteria for pro-angiogenic substances. They represent the basis for the development of novel pro-angiogenic drugs for future therapeutic angiogenesis, which might be applied for treatment of unreconstructible critical limb ischemia.
Ismail
Mahmoud
M
Department of Surgery, Universitatsmedizin Berlin, Berlin, Germany.
Henklein
Peter
P
Huang
Xiaohua
X
Braumann
Chris
C
Rückert
Ralph I
RI
Dubiel
Wolfgang
W
D043925:Angiogenesis Inducing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016758:Genes, jun; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007511:Ischemia / Q000188:drug therapy; D007797:Laminin; D009024:Morphogenesis; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011509:Proteoglycans; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology; D054322:tat Gene Products, Human Immunodeficiency Virus
D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D015696:Gene Products, tat; D007797:Laminin; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; D016755:Proto-Oncogene Proteins c-jun; C051321:SERPINE1 protein, human; D016329:Sp1 Transcription Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D046988:Proteasome Endopeptidase Complex