A synthetic peptide from transforming growth factor-beta1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats.
We investigated whether P144, a synthetic peptide from transforming growth factor-beta(1) (TGF-beta(1)) type III receptor betaglycan, exhibits cardiac antifibrotic properties.



The study was carried out in one group of 10-week-old normotensive Wistar-Kyoto rats treated with vehicle (V-WKY), one group of 10-week-old spontaneously hypertensive rats treated with vehicle (V-SHR), and one group of 10-week-old SHR treated with P144 (P144-SHR) for 12 weeks. Two more groups of 10-week-old untreated WKY and SHR were used to assess baseline values of the parameters tested. In addition, the effects of P144 on rat cardiac fibroblasts stimulated with TGF-beta(1) were also studied. Compared with V-WKY, V-SHR exhibited significant increases in the myocardial expression of phosphorylated Smad2, 38 and 42 kDa connective tissue growth factor (CTGF) isoforms, procollagen alpha1 (I) mRNA, and collagen type I protein, as well as in the expression of lysyl oxidase (LOX) mRNA and protein, collagen cross-linking and deposition. P144 administration was associated with significant reduction in all these parameters in P144-SHR. TGF-beta(1)-stimulated fibroblasts exhibited significant increases in phosphorylated Smad2, 38 and 42 kDa CTGF proteins, and procollagen alpha(1) (I) mRNA compared with control fibroblasts. No significant differences were found in these parameters between fibroblasts incubated with TGF-beta(1) and P144 and control fibroblasts.



These results show that P144 inhibits TGF-beta(1)-dependent signalling pathway and collagen type I synthesis in cardiac fibroblasts. These effects may be involved in the ability of this peptide to prevent myocardial fibrosis in SHR.
Hermida
Nerea
N
Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
López
Begoña
B
González
Arantxa
A
Dotor
Javier
J
Lasarte
Juan José
JJ
Sarobe
Pablo
P
Borrás-Cuesta
Francisco
F
Díez
Javier
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D011509:Proteoglycans / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C526316:CCN2 protein, rat; D002317:Cardiovascular Agents; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D011509:Proteoglycans; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C504795:TGF-beta1 type III receptor (730-743), human; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C071736:betaglycan; D008249:Protein-Lysine 6-Oxidase