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1.
Am J Physiol Heart Circ Physiol ; 311(3): H822-36, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27521418

ABSTRACT

The purpose of this study was to evaluate the effect of sham surgery in a minimally invasive surgical model of permanent coronary artery occlusion used to generate myocardial infarction (MI) in mice. Adult male C57BL/6J mice (3-6 mo old) were divided into five groups: day (D) 0 (no surgical operation), D1 Sham, D1 MI, D7 Sham, and D7 MI. A refined MI surgery technique was used to approach the coronary artery without the ribs being cut. Both sham and MI mice had the left ventricle (LV) exposed through a small incision. To test the effects of surgery alone, the suture was passed around the coronary artery but not ligated. The MI mice were subjected to permanent coronary artery ligation. The mice were killed at D1 or D7 postsurgical procedure. Compared with D0 no surgery controls, the D1 and D7 sham groups exhibited no surgical mortality and similar necropsy and echocardiographic variables. Surgery alone did not induce an inflammatory cell response, as evidenced by the lack of leukocyte infiltration in the sham groups. Analysis of 165 inflammatory cytokines and extracellular matrix factors in sham revealed that a minor gene response was initiated but not translated to protein levels. Collagen deposition did not occur in the absence of MI. In contrast, the D1 and D7 MI groups showed the expected robust inflammatory and scar formation responses. When a minimally invasive procedure to generate MI in mice was used, the D0 (no surgical operation) control was an adequate replacement for the use of sham surgery groups.


Subject(s)
Coronary Occlusion/metabolism , Coronary Vessels/surgery , Disease Models, Animal , Mice , Myocardial Infarction/metabolism , Myocardium/metabolism , Placebos , Animals , Collagen/metabolism , Coronary Occlusion/complications , Coronary Occlusion/pathology , Cytokines/metabolism , Extracellular Matrix/metabolism , Immunoblotting , Immunohistochemistry , Ligation , Male , Mice, Inbred C57BL , Minimally Invasive Surgical Procedures , Myocardial Infarction/etiology , Myocardial Infarction/pathology , Myocardium/pathology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
2.
J Am Coll Cardiol ; 66(12): 1364-74, 2015 Sep 22.
Article in English | MEDLINE | ID: mdl-26383724

ABSTRACT

BACKGROUND: Proteolytically released extracellular matrix (ECM) fragments, matricryptins, are biologically active and play important roles in wound healing. Following myocardial infarction (MI), collagen I, a major component of cardiac ECM, is cleaved by matrix metalloproteinases (MMPs). OBJECTIVES: This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV). METHODS: Recombinant collagen Ia1 was used in MMPs cleavage assays, the products were analyzed by mass spectrometry for identification of cleavage sites. C57BL6/J mice were given MI and animals were treated either with vehicle control or p1158/59 matricryptin. Seven days post-MI, LV function and parameters of LV remodeling were measured. Levels of p1158/59 were also measured in plasma of MI patients and healthy controls. RESULTS: In situ, MMP-2 and -9 generate a collagen Iα1 C-1158/59 fragment, and MMP-9 can further degrade it. The C-1158/59 fragment was identified post-MI, both in human plasma and mouse LV, at levels that inversely correlated to MMP-9 levels. We synthesized a peptide beginning at the cleavage site (p1158/59, amino acids 1159 to 1173) to investigate its biological functions. In vitro, p1158/59 stimulated fibroblast wound healing and robustly promoted angiogenesis. In vivo, early post-MI treatment with p1158/59 reduced LV dilation at day 7 post-MI by preserving LV structure (p < 0.05 vs. control). The p1158/59 stimulated both in vitro and in vivo wound healing by enhancing basement membrane proteins, granulation tissue components, and angiogenic factors. CONCLUSIONS: Collagen Iα1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.


Subject(s)
Collagen Type I/metabolism , Collagen Type I/therapeutic use , Myocardial Infarction/metabolism , Ventricular Remodeling , Amino Acid Sequence , Animals , Cicatrix , Collagen Type I/blood , Collagen Type I/pharmacology , Collagen Type I, alpha 1 Chain , Drug Evaluation, Preclinical , Extracellular Matrix/metabolism , Female , Human Umbilical Vein Endothelial Cells , Humans , Male , Matrix Metalloproteinase 9/metabolism , Mice, Inbred C57BL , Middle Aged , Molecular Sequence Data , Neovascularization, Physiologic , Random Allocation , Wound Healing
3.
J Mol Cell Cardiol ; 76: 218-26, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25240641

ABSTRACT

Periodontal disease (PD) strongly correlates with increased mortality post-myocardial infarction (MI); however, the underlying mechanisms are unknown. Matrix metalloproteinase (MMP)-9 levels directly correlate with dysfunction and remodeling of the left ventricle (LV) post-MI. Post-MI, MMP-9 is produced by leukocytes and modulates inflammation. We have shown that exposure to Porphyromonas gingivalis lipopolysaccharide (PgLPS), an immunomodulatory molecule identified in PD patients, increases LV MMP-9 levels in mice and leads to cardiac inflammation and dysfunction. The aim of the study was to determine if circulating PgLPS exacerbates the LV inflammatory response post-MI through MMP-9 dependent mechanisms. We exposed wild type C57BL/6J and MMP-9(-/-) mice to PgLPS (ATCC 33277) for a period of 28 days before performing MI, and continued to deliver PgLPS for up to 7 days post-MI. We found systemic levels of PgLPS 1) increased MMP-9 levels in both plasma and infarcted LV resulting in reduced wall thickness and increased incidence of LV rupture post-MI and 2) increased systemic and local macrophage chemotaxis leading to accelerated M1 macrophage infiltration post-MI and decreased LV function. MMP-9 deletion played a protective role by attenuating the inflammation induced by systemic delivery of PgLPS. In conclusion, MMP-9 deletion has a cardioprotective role against PgLPS exposure, by attenuating macrophage mediated inflammation.


Subject(s)
Lipopolysaccharides/pharmacology , Matrix Metalloproteinase 9/blood , Myocardial Infarction/immunology , Porphyromonas gingivalis/immunology , Animals , Bacteroidaceae Infections/blood , Bacteroidaceae Infections/enzymology , Bacteroidaceae Infections/immunology , Cell Movement , Female , Gene Expression , Inflammation Mediators/metabolism , Macrophages/immunology , Male , Matrix Metalloproteinase 9/genetics , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/blood , Myocardial Infarction/enzymology , Periodontal Diseases/blood , Periodontal Diseases/complications , Periodontal Diseases/microbiology
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