Differential role of TGF-beta1/bFGF and ET-1 in graft fibrosis in heart failure patients.
Collagen overproduction characteristic for dilated cardiomyopathy (DCM) is coregulated by endothelin (ET)-1, transforming growth factor (TGF)-beta1, basic fibroblast growth factor (bFGF) and matrix metalloproteases (MMPs). Whether these molecules affect grafts transplanted to heart failure patients is unknown. In 67 idiopathic DCM patients, 31 patients with ischemic cardiomyopathy (ICM) and 16 controls, the myocardial bFGF, TGF-beta1, pro-collagen (PrCol) type 1 (PrCol1-alpha1, -alpha2) and MMP expressions were examined using real-time RT-PCR or Western blotting. mRNA expression was measured in grafts for 1 year. TGF-beta1/bFGF stimulation or gene silencing was used to examine their effect on collagen synthesis in cardiac tissue cultures. TGF-beta1 and PrCol1 were upregulated in DCM only, while bFGF was upregulated in both groups versus controls. TGF-beta1 downregulated MMP-1 and upregulated collagen 1, whereas bFGF upregulated MMP-13 in DCM tissue. Post-transplant PrCol1-alpha1, -alpha2 and ET-1 mRNA increased over time in grafts of DCM patients only, while other factors returned to control baseline levels in DCM and ICM. These data indicate that cardiac transplantation corrects the dysregulated TGF/bFGF/MMP-1/MMP-13, but not the excess collagen and ET-1 synthesis in cardiac grafts transplanted to DCM patients. ET-1 might be a major pathologic trigger for graft fibrosis in DCM.
Aharinejad
Seyedhossein
S
Department of Cardio-Thoracic Surgery, Vienna Medical University, Waehringer Guertel 18-20, A-1090 Vienna, Austria. seyedhossein.aharinejad@meduniwien.ac.at
Krenn
Katharina
K
Paulus
Patrick
P
Schäfer
Romana
R
Zuckermann
Andreas
A
Grimm
Michael
M
Abraham
Dietmar
D
D000328:Adult; D001706:Biopsy; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D017364:Collagenases / Q000096:biosynthesis; D015536:Down-Regulation; D004452:Echocardiography; D019332:Endothelin-1 / Q000096:biosynthesis*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis*; D005355:Fibrosis / Q000473:pathology*; D020868:Gene Silencing; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019332:Endothelin-1; D007166:Immunosuppressive Agents; C508960:TGFB1 protein, human; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1