scholarly journals Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling

2011 ◽  
Vol 301 (4) ◽  
pp. H1656-H1666 ◽  
Author(s):  
Juozas A. Zavadzkas ◽  
Rupak Mukherjee ◽  
William T. Rivers ◽  
Risha K. Patel ◽  
Evan C. Meyer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Transforming Growth Factor ◽  
Biological Effects ◽  
Left Ventricular ◽  
Lv Function ◽  
Membrane Type

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP+/−), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1-MMP+/− compared with WT. LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT post-MI and was higher in the MT1-MMP+/− mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP+/− group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP+/− group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP+/− group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process.

scholarly journals Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction

2018 ◽  
Vol 314 (2) ◽  
pp. H224-H235 ◽  
Author(s):  
Cesar A. Meschiari ◽  
Mira Jung ◽  
Rugmani Padmanabhan Iyer ◽  
Andriy Yabluchanskiy ◽  
Hiroe Toba ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Wound Healing ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 9 ◽  
Sequencing Analysis ◽  
Metalloproteinase 9 ◽  
Cardiac Wound Healing

Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice ( n = 10–21 mice/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day 7 post-MI, aging TG mice showed improved diastolic properties and remodeling index compared with WT mice (both P < 0.05). Macrophage numbers were higher in TG than WT mice at days 0 and 7 post-MI, and the post-MI increase was due to elevated cluster of differentiation 18 protein levels (all P < 0.05). RNA sequencing analysis of cardiac macrophages isolated from day 7 post-MI infarcts identified 1,276 statistically different (all P < 0.05) genes (994 increased and 282 decreased in TG mice). Reduced expression of vascular endothelial growth factor A, platelet-derived growth factor subunit A, and transforming growth factor-β3, along with elevated expression of tissue inhibitor of MMP-4, in macrophages revealed mechanisms of indirect downstream effects on fibroblasts and neovascularization. While collagen accumulation was enhanced in TG mice compared with WT mice at days 0 and 7 post-MI ( P < 0.05 for both), the post-MI collagen cross-linking ratio was higher in WT mice ( P < 0.05), consistent with increased diastolic volumes. Vessel numbers [by Griffonia ( Bandeiraea) simplicifolia lectin I staining] were decreased in TG mice compared with WT mice at days 0 and 7 post-MI ( P < 0.05 for both). In conclusion, macrophage-derived MMP-9 improved post-MI cardiac wound healing through direct and indirect mechanisms to improve diastolic physiology and remodeling.NEW & NOTEWORTHY Aging mice with macrophage overexpression of matrix metalloproteinase-9 have increased macrophage numbers 7 days after myocardial infarction, resulting in improved diastolic physiology and left ventricular remodeling through effects on cardiac wound healing.

scholarly journals Pressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis

2012 ◽  
Vol 302 (7) ◽  
pp. H1429-H1437 ◽  
Author(s):  
Michael R. Zile ◽  
Catalin F. Baicu ◽  
Robert E. Stroud ◽  
An Van Laer ◽  
Jazmine Arroyo ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Left Atrial ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Luciferase Expression ◽  
Promoter Activation ◽  
Membrane Type ◽  
Expression And Activity

Increased myocardial extracellular matrix collagen represents an important structural milestone during the development of left ventricular (LV) pressure overload (PO); however, the proteolytic pathways that contribute to this process are not fully understood. This study tested the hypothesis that membrane type 1-matrix metalloproteinase (MT1-MMP) is directly induced at the transcriptional level in vivo during PO and is related to changes in LV collagen content. PO was induced in vivo by transverse aortic constriction in transgenic mice containing the full length human MT1-MMP promoter region ligated to luciferase (MT1-MMP Prom mice). MT1-MMP promoter activation (luciferase expression), expression, and activity; collagen volume fraction (CVF); and left atrial dimension were measured at 1 ( n = 8), 2 ( n = 12), and 4 ( n = 17) wk following PO. Non-PO mice ( n = 10) served as controls. Luciferase expression increased by fivefold at 1 wk, fell at 2 wk, and increased again by ninefold at 4 wk of PO ( P < 0.05). MT1-MMP expression and activity increased at 1 wk, fell at 2 wk, and increased again at 4 wk after PO. CVF increased at 1 wk, remained unchanged at 2 wk, and increased by threefold at 4 wk of PO ( P < 0.05). There was a strong positive correlation between CVF and MT1-MMP activity ( r = 0.80, P < 0.05). Left atrial dimension remained unchanged at 1 and 2 wk but increased by 25% at 4 wk of PO. When a mechanical load was applied in vitro to LV papillary muscles isolated from MT1-MMP Prom mice, increased load caused MT1-MMP promoter activation to increase by twofold and MT1-MMP expression to increase by fivefold ( P < 0.05). These findings challenge the canonical belief that PO suppresses overall matrix proteolytic activity, but rather supports the concept that certain proteases, such as MT1-MMP, play a pivotal role in PO-induced matrix remodeling and fibrosis.

scholarly journals Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas

2004 ◽  
Vol 6 (3) ◽  
pp. 188-199 ◽  
Author(s):  
Timothy E. Van Meter ◽  
William C. Broaddus ◽  
Harcharan K. Rooprai ◽  
Geoffrey J. Pilkington ◽  
Helen L. Fillmore
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Matrix Metalloproteinase ◽  
Epidermal Growth ◽  
Membrane Type
Sign in / Sign up

Export Citation Format

Share Document