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1 Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States; RHJ Department of Veterans Affairs Medical Center, Charleston, South Carolina, United States
2 Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, United States
3 Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, United States
4 RHJ Department of Veterans Affairs Medical Center, Charleston, South Carolina, United States; Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, United States
* To whom correspondence should be addressed. E-mail: wilburnm{at}musc.edu.
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 non-failing, 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 2-fold in DCM FIBROS compared to reference normal (p<0.05) and remained lower in polyribosomal fractions (ie; 15.7±5.2 vs 1.4±0.6% in polysomal fraction 6, p<0.05). These differences in DCM MT1-MMP FIBRO 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 ion DCM fibroblasts may provide the basis for developing cell specific pharmacological targets for control of MT1-MMP expression.
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