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Thoracic aortic aneurysms (TAAs) develop as a result of dysregulated extracellular matrix remodeling mediated by several matrix metalloproteinases (MMPs). Membrane type-1 MMP (MT1-MMP) is the prototypical member of a unique family of membrane-bound MMPs, possessing multiple substrates and functions. The present study tested the hypothesis that MT1-MMP expression, abundance, and activity would be elevated during TAA development and that this protease is produced primarily by mesenchymal cells within the thoracic aorta. Descending thoracic aortas were harvested from C57BL/6J mice at multiple time points (2, 4, 8, and 16 wk, n = 15 each) post-TAA induction (0.5M Ca[C1.sub.2], 15 rain) and compared with reference controls (n = 15). The expression and abundance of MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase (TIMP)-2 were assessed by quantitative PCR and immunoblot analysis. MT 1-MMP activity was determined by fluorescent peptide assay. MT1-MMP was localized within the aortic wall by immunohistochemistry. MT1-MMP abundance and localization in live animals (8 wk post-TAA induction vs. control) was determined by microultrasound imaging with an MT1-MMP-targeted microbubble contrast agent. Aortic diameter was increased 172 [+ or -] 7% at 16 wk post-TAA induction (P < 0.05). MT1-MMP and MMP-2 mRNA levels were elevated at 2 wk post-TAA induction (P < 0.05). MT1MMP protein abundance increased progressively to a maximum of 178 [+ or -] 26% at 16 wk post-TAA induction, whereas MMP-2 and TIMP-2 peaked at 2 wk post-TAA induction (526 [+ or -] 93% and 376 [+ or -] 48%, respectively, P < 0.05). MT1-MMP colocalized with fibroblasts, and MT 1-MMP-targeted contrast binding was elevated in 8-wk TAA-induced mice versus control mice (217 [+ or -] 53% vs. 81 [+ or -] 8%, P < 0.05). In conclusion, these novel results suggest that MT1-MMP plays a dynamic multifunctional role in TAA development and, therefore, may provide a significant target for therapeutic strategies. fibroblast; vascular remodeling; extracellular matrix; microbubble contrast doi: 10.1152/ajpheart.00028.2010.

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 heart failure; extracellular matrix; proteases

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-Ml remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 mg x [kg.sup.-1] x [day.sup.-1]) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/ MMPi (n = 10), TIMP1-KO-MI/MMPi (n = 10), WT-MI (n = 22), and TIMP1-KO-MI (n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT (n = 20) and TIMP1-KO (n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 [+ or -] 2 and 40 [+ or -] 2 [micro]l, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 [+ or -] 2 vs. 61 [+ or -] 5 [micro]l. P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 [+ or -] 2 and 36 [+ or -] 2 [micro]l, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice (P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically 'rescued' by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI. transgenic model; heart failure; myocardial hypertrophy

The role of adenosine and protein kinase C (PKC) bioactivity in promoting the myocardial protective effects of ischemic preconditioning was analyzed in monolayer cultures of human pediatric myocytes. Simulated ischemia in monolayer cultures of human pediatric myocytes indicated the role of myocyte adenosine secretions in exerting an endogenously derived form of protection through binding to sarcolemmal adenosine receptors. Furthermore, the cardioprotective effects of ischemic preconditioning involved the activation of protein kinase C by adenosine.

Past studies have identified that a unique type of matrix metalloproteinase, the membrane-type- 1 MMP (MT 1 -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 MTI- MMP protein increased by over 190% from reference normal FIBROS (both P < 0.05). MTI-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 MTI-MMP FIBROS transcription and translation persisted throughout passages 2–5. The unique findings from this study demonstrated that elevated steady-state MTI-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 MT 1 -MMP expression. [ABSTRACT FROM AUTHOR]