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Am J Physiol Cell Physiol 293: C1362-C1373, 2007. First published August 1, 2007; doi:10.1152/ajpcell.00545.2006
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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy

Laura S. Spruill,1,2 Abigail S. Lowry,3 Robert E. Stroud,3 Christina E. Squires,3 Ira M. Mains,3 English C. Flack,3 Christy Beck,3 John S. Ikonomidis,3 A. Jackson Crumbley,3 Paul J. McDermott,1,2 and Francis G. Spinale2,3

1Division of Cardiology, Department of Medicine, Medical University of South Carolina, 2Ralph H. Johnson Department of Veterans Affairs Medical Center, and 3Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina

Submitted 24 October 2006 ; accepted in final form 28 July 2007

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.

heart failure; extracellular matrix; proteases


Address for reprint requests and other correspondence: F. G. Spinale, Cardiothoracic Surgery, Rm. 625, Strom Thurmond Research Bldg., 770 MUSC Complex, Medical Univ. of South Carolina, 114 Doughty St., Charleston, SC 29425 (e-mail: wilburnm{at}musc.edu)






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