Abstract 515: Membrane type 1-matrix metalloproteinase cooperates with KrasG12D to promote pancreatic fibrosis through transforming growth factor-β activation of pancreatic stellate cells

2011 ◽  
Author(s):  
Seth B. Krantz ◽  
Mario S. Shields ◽  
Surabhi Dangi-Garimella ◽  
Eric C. Cheon ◽  
Morgan R. Barron ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Membrane Type

scholarly journals New aspects of formation and progression of pancreatic fibrosis in pancreatitis

2019 ◽  
Vol 43 (2) ◽  
pp. 20-24
Author(s):  
V. A. Akhmedov ◽  
O. V. Gaus
Keyword(s):  
Extracellular Matrix ◽  
Chronic Pancreatitis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Main Components ◽  
Acute And Chronic Pancreatitis

Fibrosis formation is a dynamic process during which the formation of an extracellular matrix takes place in interstitial spaces and areas where the main components of exocrine pancreatic function (acinar cells) are damaged. According to studies, the biggest role in the formation of pancreatic fibrosis upon chronic pancreatitis is played by various types of effector cells, such as fibroblasts, myofibroblasts and fibrocytes, while fibroblasts and myofibroblasts are the key fibrosis cells responsible for the secretion of extracellular matrix. Activated pancreatic stellate cells become main components of fibrosis formation in patients with chronic pancreatitis, synthesizing transforming growth factor-β, fibroblast growth factor, which leads to enhanced synthesis of extracellular matrix. The presented review highlights molecular mechanisms (Rho-kinase, mitogen-activating protein kinase, transforming growth factor-β, associated with the protein encoded by SMAD in humans, phosphatidylinositol-3 kinase), which play an important role in the activation of pancreatic stellate cells and launching the phenomenon of pancreatic fibrogenesis. The presented data opens up prospects for the development of diagnostic areas with the search for new markers for the diagnosis of acute and chronic pancreatitis along with development of new therapeutic options for the pathogenetic therapy of patients with acute and chronic pancreatitis based on the results obtained.

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.

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