Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy.
Past studies have identified that a unique type of matrix metalloproteinase, the membrane-type-1 MMP (MT1-MMP), is increased within the left ventricle (LV) of patients with dilated cardiomyopathy (DCM). However, the cellular and molecular basis for this induction of MT1-MMP with DCM is unknown. LV myocardial biopsies from nonfailing, reference normal patients (defined as LV ejection fraction >50%, elective coronary bypass surgery, no perfusion defect at biopsy site, n = 6) and DCM patients (LV ejection fraction <20%, at transplant, n = 5) were used to establish fibroblast cultures (FIBROS). Confluent LV FIBROS from culture passages 2-5 were measured with respect to MT1-MMP mRNA and protein levels and the distribution of the MT1-MMP mRNA pool in ribosomal fractions. Total MT1-MMP mRNA within DCM FIBROS increased by over 140%, and MT1-MMP protein increased by over 190% from reference normal FIBROS (both P < 0.05). MT1-MMP mRNA in monosome fractions decreased by over twofold in DCM FIBROS compared with reference normal (P < 0.05) and remained lower in polyribosomal fractions (i.e., 15.7 +/- 5.2 vs. 1.4 +/- 0.6% in polysomal fraction 6, P < 0.05). These differences in DCM MT1-MMP FIBROS transcription and translation persisted throughout passages 2-5. The unique findings from this study demonstrated that elevated steady-state MT1-MMP mRNA and protein levels occurred in DCM FIBROS despite a decline in translational deficiency. These phenotypic changes in DCM fibroblasts may provide the basis for developing cell specific pharmacological targets for control of MT1-MMP expression.
Spruill
Laura S
LS
Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Lowry
Abigail S
AS
Stroud
Robert E
RE
Squires
Christina E
CE
Mains
Ira M
IM
Flack
English C
EC
Beck
Christy
C
Ikonomidis
John S
JS
Crumbley
A Jackson
AJ
McDermott
Paul J
PJ
Spinale
Francis G
FG
D000328:Adult; D001706:Biopsy; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016277:Ventricular Function, Left
D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14