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.

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 Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model

2020 ◽  
Vol 134 (18) ◽  
pp. 2521-2534 ◽  
Author(s):  
Vianne Nsengiyumva ◽  
Smriti M. Krishna ◽  
Corey S. Moran ◽  
Joseph V. Moxon ◽  
Susan K. Morton ◽  
...  
Keyword(s):  
Vitamin D ◽  
Extracellular Matrix ◽  
Mouse Model ◽  
Vitamin D Deficiency ◽  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Matrix Metalloproteinase 2 ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Abdominal Aortic

Abstract Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

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.

Abstract 1707: Analysis Of Extracellular Matrix Remodeling On Endomyocardial Biopsies From Patients With Inflammatory Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Olga Lettau ◽  
Susanne Rutschow ◽  
Sebastian Jaeger ◽  
Uwe Kuehl ◽  
Kerstin Puhl ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Collagen Type ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Myocardial Inflammation ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Inflammatory Cardiomyopathy ◽  
Ventricular Ejection Fraction

Introduction: The biopsy based analyse, with histological, immunohistological and molecular biological analysis of myocardial tissues, represents the only possible tool to investigate the basement of inflammatory cardiomyopathy. Since development of this disease assume involvement of extracellular matrix remodelling, the analyze of this process were aimed in this article. Methods and results: Endomyocardial biopsies from patient with inflammatory cardiomyopathy (n=170) were analysed by RT-PCR, Furthermore, histological, immunohistological and biochemical methods (ELISA) were used to estimate the matrix proteins amount in myocardial tissues (n=36). All results were obtained by comparison of patient groups regarding to left ventricular ejection fraction (LVEF), EF>60 versus EF<30. EF<30 group featured significaly increased inflammation cells per surface area: CD3 (p<0.001), CD11a (p<0.02), CD45 (p<0.02), Mac1 (p<0.02) and HLA (p<0.01). The gene expression revealed an increased transcripts number of IL-2 (p<0.01), IL-5 (p<0.01), IL-6 (p<0.02), INF beta (p<0.039), Collagen type I (p<0.001), III (p<0.0014) and IV (p<0.0004) as well Laminin (p<0.001). On the protein level ICTP (p<0.04), MMP9 (p<0.04) and TIMP I (p<0.01) were significaly increased in this group in comparison with EF>60 group. The escalating number of active CD3 cells correlated positively with BNP (ρ=0.624, p<0.0091), adhesion cell number ICAM (ρ=0.682, p<0.01) and VCAM (ρ=0.475, p<0.01) and with uPA (ρ =0.265, p<0.013), as well as with increased quantity of collagen type III per section area (ρ=0.632, p<0.01). The expanded abundance of type I collagen products was clearly dependent of the expression of collagen I gene (ρ=0.575, p<0.002) and uPA (ρ=0.544, p<0.004). Precise correlation between the amount of MMP 9 protein and downward EV values (ρ=− 0.4133, p<0.0073) was also observed in the patient group with EF<30. Conclusion: Myocardial inflammation lead to an imbalance in the MMP/TIMP system with development of myocardial fibrosis with significant correlation to LV-dysfunction. Extracellular matrix remodeling with an imbalance in the MMP/TIMP system plays an important role in the development of left ventricular dysfunction in inflammatory heart disease

Left Ventricular Extracellular Matrix Remodeling in Dogs with Right Ventricular Apical Pacing

2010 ◽  
Vol 21 (10) ◽  
pp. 1142-1149 ◽  
Author(s):  
JIH-MIN LIN ◽  
LING-PING LAI ◽  
CHIH-SHENG LIN ◽  
NAI-KUAN CHOU ◽  
CHIH-YUAN CHIU ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Right Ventricular Apical Pacing

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

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