Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction

Abstract

Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n ϭ 63) and MMP-9 null (n ϭ 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITClabeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated ␣v␤3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0 -40% nonischemic) was higher in MMP-9 null than in WT mice (383 Ϯ 162% vs. 250 Ϯ 118%, respectively; P ϭ 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response. leukocytes; remodeling; imaging REMODELING OF THE LEFT VENTRICLE (LV) postmyocardial infarction (post-MI) evokes changes to both cellular and extracellular matrix components to progressively alter LV structure and function (35). Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that can cleave all components of the extracellular matrix (ECM) and thereby exert influence on LV remodeling. MMPs are elevated after MI, and a cause and effect relationship between MMPs and LV remodeling has been demonstrated through the use of MMP inhibitors and MMP-null mice (23,38,55). In particular, MMP-9 is a 92-kDa gelatinase upregulated acutely post-MI, and MMP-9 gene deletion results in attenuated LV remodeling after MI (6, 22). Thus MMP-9 likely contributes to adverse LV remodeling post-MI.For the purposes of this study, we use neovascularization and angiogenesis interchangeably according to the following previously assigned definition: the sprouting of new vessels at the capillary level (48). MMPs have also demonstrated roles in neovascularization, and MMP inhibition has been postulated to inhibit the angiogenic process (43). Clinical trials with MMP inhibitors, however, have suggested that MMP inhibition may promote, rather than inhibit, neovascularization (2). MMP-9 is a specific MMP that has been implicated in angiogenesis, and the macrophage is one of several cell types that express MMP-9 post-MI (46). The exact role of MMPs, particularly MMP-9, in post-MI neovascularization is not clear. The MMP-9 substrate portfolio is broad and includes both angiogenic a...

Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

“…In this regard, a possible dual role of MMP9 in angiogenesis that depends on the endogenous tissue vascularization has been observed by other authors, as this protease was required for ischemia-induced angiogenesis after hindlimb ischemia, 15 whereas in cardiac tissue MMP9-deficiency facilitated angiogenesis after myocardial infarction. 16 The most important finding of our study, which we believe will be of great importance to the development of future cell-based neurorepair strategies after stroke, is the MMP9 tissue dependency after EPC therapy. To date, several different subsets of EPC populations have been demonstrated to have therapeutic potential in experimental models of cerebral ischemia.…”

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction

“…MMPs 9 and 13 have been linked to the proteolytic activation of latent transforming growth factor ␤, a strong inducer of interstitial fibrosis, and to postinfarct myocardial rupture. These MMPs are strongly induced in the heart by TNF and other proinflammatory stimuli present at elevated levels in the failing heart (1,10,15,22,23,28,32,38,(48)(49)(50).…”

“…Studies of mice with a targeted deletion of mmp9 clearly implicate this factor in not only left ventricular dilation but also in inhibition of neo-angiogenesis postinfarct (1,10,15,22,23,38). Other studies suggest MMP13 may also be important in late progression of remodeling (46).…”

“…Post-myocardial infarction, in addition to hypertrophy of surviving cardiomyocytes, remodeling of the extracellular matrix occurs, particularly within the territory of the infarct, as lost myocytes are replaced by fibrous tissue (22,23). Key to this remodeling process is the production and release of matrix metalloproteases (MMPs) from both resident cells, especially cardiac fibroblasts, and infiltrating leukocytes.…”

ACE inhibitors to block MMP-9 activity: New functions for old inhibitors

“…Ample evidence has demonstrated a direct cause and effect relationship between MMP-9 and LV remodeling: 1) MMP-9 levels increase early post-MI [12], 2) MMP inhibition improves post-MI outcomes [13], and 3) MMP-9 gene deletion reduces remodeling and stimulates post-MI angiogenesis. [14] Furthermore, Blankenberg and colleagues have shown that MMP-9 is also a novel predictor of cardiovascular mortality, as patients with coronary artery disease who had the highest MMP-9 levels at baseline showed the greatest cardiovascular mortality rates at follow-up. [15] While global non-selective MMP inhibition studies have not fared well, strategies that specifically limit MMP-9 activity may prove beneficial.…”