Cardiac restricted overexpression of membrane type-1 matrix metalloproteinase causes adverse myocardial remodeling following myocardial infarction.
The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.
Spinale
Francis G
FG
Medical University of South Carolina, Ralph H Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425, USA.
Mukherjee
Rupak
R
Zavadzkas
Juozas A
JA
Koval
Christine N
CN
Bouges
Shenikqua
S
Stroud
Robert E
RE
Dobrucki
Lawrence W
LW
Sinusas
Albert J
AJ
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D020257:Ventricular Remodeling
D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; C507096:Mmp14 protein, mouse; D003094:Collagen; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14