Dataset Information

A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis.

ABSTRACT: 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).This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV).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.In situ, MMP-2 and -9 generate a collagen I?1 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.Collagen I?1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.

SUBMITTER: Lindsey ML

PROVIDER: S-EPMC4575409 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis.

Lindsey Merry L ML Iyer Rugmani Padmanabhan RP Zamilpa Rogelio R Yabluchanskiy Andriy A DeLeon-Pennell Kristine Y KY Hall Michael E ME Kaplan Abdullah A Zouein Fouad A FA Bratton Dustin D Flynn Elizabeth R ER Cannon Presley L PL Tian Yuan Y Jin Yu-Fang YF Lange Richard A RA Tokmina-Roszyk Dorota D Fields Gregg B GB de Castro Brás Lisandra E LE

Journal of the American College of Cardiology 20150901 12

<h4>Background</h4>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).<h4>Objectives</h4>This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV).<h4>Methods</h4>Recombinant collagen Ia1 was used in MMPs ...[more]

PMID: 26383724

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Project description:We report a genome-wide survey of early responses of the mouse heart transcriptome to acute myocardial infarction (AMI). For three regions of the left ventricle (LV), namely ischemic/infarcted tissue (IF), the surviving LV free wall (FW) and the interventricular septum (IVS), 36,899 transcripts were assayed at six time points from 15 min to 48 h post-AMI in both AMI and sham surgery mice. For each transcript, temporal expression patterns were systematically compared between AMI and sham groups, which identified 515 AMI-responsive genes in IF tissue, 35 in the FW, 7 in the IVS, with three genes induced in all three regions. Using the literature, we assigned functional annotations to all 519 nonredundant AMI-induced genes and present two testable models for central signaling pathways induced early post-AMI. First, the early induction of 15 genes involved in assembly and activation of the activator protein-1 (AP-1) family of transcription factors implicates AP-1 as a dominant regulator of earliest post-ischemic molecular events. Second, dramatic increases in transcripts for arginase 1 (ARG1), the enzymes of polyamine biosynthesis and protein inhibitor of nitric oxide synthase (NOS) activity indicates that NO production may be regulated, in part, by inhibition of NOS and coordinate depletion of the NOS substrate, L-arginine. ARG1 was the single most highly induced transcript in the database (121-fold in IF region) and its induction in heart has not been previously reported. Keywords: heart attack, mouse, time course, regional responses We report temporal and regional changes in steady state mRNA levels in the mouse LV following a surgically-induced AMI. Three regions of the infarcted LV were surveyed: IF, FW and IVS. For each region, mRNA levels were assayed at t=0 and six time points after occlusion of the left anterior descending coronary artery (t = 15 min, 1 h, 4 h, 12 h, 24 h, 48 h). As control, an identical time course was carried out in the mouse LV after sham surgery in which the suture was passed under the artery, but not ligated. For sham surgical mice and naïve mice (t=0), the IVS and the LV free wall were harvested and assayed. The AMI and sham time courses were repeated for a total of two independent repetitions of the experiment. For each repetition, 96 GeneChips were hybridized. Thus, for two repetitions, 192 GeneChips (2 x 96) were hybridized. In addition, the naïve time point was assayed a second time during Repetition 1 for six additional GeneChips (two tissues x three chips). The overall total number of samples is 198 GeneChips (192 + 6). Total RNA was isolated from each individual tissue sample. Equal weights of total RNA from 4-10 mice were combined for each LV region, time point and treatment. Copy RNA mixtures were synthesized from each total RNA pool and hybridized to the Affymetrix GeneChip set MG U74 v2 (A, B, and C) that carries 36,899 probe sets. The global normalization of fluorescence emissions for the 198 GeneChips used in this study and their conversion to relative transcript concentrations measured in relative fluorescence units (RFU) was conducted using Robust Multi-array Averaging (RMA; www.bioconductor.org). Each of the 198 Accessions is titled as follows: time point / treatment / tissue, repetition, GeneChip. The additional assays of naïve mice in Repetition 1 are labeled “Naive2”.

Dataset Information

A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis.

Publications

A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis.

Similar Datasets

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