MMP inhibition modulates TNF-α transgenic mouse phenotype early in the development of heart failure

2002 ◽  
Vol 282 (3) ◽  
pp. H983-H989 ◽  
Author(s):  
Yun You Li ◽  
Toshiaki Kadokami ◽  
Ping Wang ◽  
Charles F. McTiernan ◽  
Arthur M. Feldman
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Critical Role ◽  
Left Ventricular ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Insoluble Collagen ◽  
Mmp Inhibitor ◽  
Tnf Α ◽  
And Function

Myocardial extracellular matrix remodeling regulated by matrix metalloproteinases (MMPs) is implicated in the progression of heart failure. We hypothesized that MMP inhibition may modulate extracellular matrix remodeling and prevent the progression of heart failure. The effects of the MMP inhibitor BB-94 (also known as batimastat) on MMP expression, collagen expression, collagen deposition, collagen denaturation, and left ventricular structure and function in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor-α (TNF-α) (TNF1.6) were assessed. The results showed that BB-94 reduced the expression of collagens, increased insoluble collagen and the ratio of undenatured to total soluble collagen, and prevented myocardial hypertrophy and diastolic dysfunction in young TNF1.6 mice. Furthermore, the treatment significantly improved cumulative survival of TNF1.6 mice. However, MMP inhibition did not have salutary effects on ventricular size and function in old mice with established heart failure. The results suggest that MMP activation may play a critical role in changes of myocardial function through the remodeling of extracellular matrix, and MMP inhibition may serve as a potential therapeutic strategy for heart failure, albeit within a narrow window during the development of heart failure.

scholarly journals A Potential Role for MMPs during the Formation of Non-Neurogenic Placodes

2018 ◽  
Vol 6 (3) ◽  
pp. 20 ◽  
Author(s):  
Paige Drake ◽  
Tamara Franz-Odendaal
Keyword(s):  
Extracellular Matrix ◽  
Mammary Gland ◽  
Matrix Metalloproteinases ◽  
Potential Role ◽  
Critical Role ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lens Development ◽  
Cell Behaviors ◽  
Placode Formation

The formation of non-neurogenic placodes is critical prior to the development of several epithelial derivatives (e.g., feathers, teeth, etc.) and their development frequently involves morphogenetic proteins (or morphogens). Matrix metalloproteinases (MMPs) are important enzymes involved in extracellular matrix remodeling, and recent research has shown that the extracellular matrix (ECM) can modulate morphogen diffusion and cell behaviors. This review summarizes the known roles of MMPs during the development of non-neurogenic structures that involve a placodal stage. Specifically, we discuss feather, hair, tooth, mammary gland and lens development. This review highlights the potential critical role MMPs may play during placode formation in these systems.

scholarly journals 4-Methylumbelliferone Attenuates Macrophage Invasion and Myocardial Remodeling in Pressure-Overloaded Mouse Hearts

Hypertension ◽  
2021 ◽  
Author(s):  
Katarzyna Hackert ◽  
Susanne Homann ◽  
Shakila Mir ◽  
Arne Beran ◽  
Simone Gorreßen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Pressure Overload ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Cardiac Wall

Cardiac wall stress induces local and systemic inflammatory responses that are increasingly recognized as key modulators of extracellular matrix remodeling. Hyaluronic acid interacts with immune cells and mesenchymal cells thereby modulating profibrotic signals. Here we tested the hypothesis that 4-methylumbelliferone (4-MU), an inhibitor of hyaluronic acid synthesis, would attenuate inflammation and extracellular matrix remodeling of pressure-overloaded myocardium in C57BL/6J male mice fed with 4-MU and subjected to TAC (transverse aortic constriction) surgery. Flow cytometry of immune cells showed TAC-induced leukocytosis due to an increase of neutrophils and monocytes. 4-MU strongly attenuated both circulating and cardiac leukocyte numbers 3 days after TAC. In the hearts, 4-MU reduced the number of CCR2 − resident macrophages. At later time points, 4-MU also prevented the infiltration of heart tissue by bone marrow-derived circulating monocytes leading to reduced cardiac macrophage counts even 7 weeks after TAC. The long-term attenuation of macrophage-driven inflammation was associated with less myocardial fibrosis in 4-MU-treated compared with untreated mice. Unexpectedly, 4-MU also reduced the development of left ventricular hypertrophy and increased cardiac output after TAC without affecting blood pressure. The data demonstrate that 4-MU reduces both resident and invading cardiac macrophages and may be a promising agent to alleviate pressure-overload induced myocardial damage.

scholarly journals Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

2015 ◽  
Vol 308 (11) ◽  
pp. H1391-H1401 ◽  
Author(s):  
Santhosh K. Mani ◽  
Christine B. Kern ◽  
Denise Kimbrough ◽  
Benjamin Addy ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Left Ventricular ◽  
Class I ◽  
Matrix Metalloproteinase 2 ◽  
Lv Function ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lv Remodeling

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

Abstract 4952: Differential Expression in the Determinants of Extracellular Matrix Remodeling in Pediatric and Adult Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tain-Yen Hsia ◽  
Jeremy M Ringewald ◽  
Robert E Stroud ◽  
Michael C Graves ◽  
Scott M Bradley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dilated Cardiomyopathy ◽  
Cell Lineage ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Matrix Remodeling ◽  
Adult Age ◽  
Membrane Type ◽  
And Function ◽  
Aggressive Clinical Course

Ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in pediatric and adult patients, but a more aggressive clinical course often occurs with pediatric DCM. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tests the hypothesis that different MMP/TIMP profiles occur in pediatric and adult DCM patients. Left ventricular samples were taken from pediatric (age 12±4 yr; n=5) and adult (age 63±3 yr; n=11) patients during heart transplantation for DCM. Myocardial levels were quantified for all MMP classes: gelatinases (MMP-2, -9), collagenases (MMP-8, -13), lysins (MMP-7), membrane-type (MT1-MMP), and for all 4 known TIMPs. Patients with structural or ischemic etiologies of DCM were excluded. Compared to adults, MMP-8 levels increased by over 350% (Figure ), and MMP-7 and MT1-MMP levels (75±9% and 76±9%, respectively; p<0.05) were lower in pediatric patients. In contrast, pediatric TIMP-1 levels were reduced by over 50% (Figure). Pediatric DCM patients manifest a robust increase in MMP-8, which degrades all components of the extracellular matrix, and a decrease in TIMP-1, which inhibits MMP-8. This heightened MMP-8/TIMP-1 ratio would favor aggressive matrix remodeling in pediatric DCM. Since MMP-8 is primarily expressed by macrophage cell lineage, a unique proteolytic program may exist in pediatric DCM. These distinct differences in determinants of myocardial matrix structure and function likely contribute to the more progressive nature of DCM in children.

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