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Age effects in the extracellular matrix (ECM) proteome of the mouse left ventricle

ABSTRACT: Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. MMP-9 has the strongest link to development of cardiac dysfunction. Aging is associated with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged mice. Based on label-free mass spectrometry analyses, MMP-9 dependent age-related changes were found in the mouse cardiac ECM proteome, suggesting MMP-9 as a possible therapeutic target for the aging patient

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Susan Weintraub

LAB HEAD: Susan T. Weintraub

PROVIDER: PXD002488 | Pride | 2018-07-05

REPOSITORIES: Pride

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			Action	DRS
	01_130305ML01_B1.raw	Raw
	01_130418ML01_D1.raw	Raw
	02_130312ML01_A1.raw	Raw
	02_130419ML01_C1.raw	Raw
	07_130418ML02_D4.raw	Raw

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Publications

Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart.

Padmanabhan Iyer Rugmani R Chiao Ying Ann YA Flynn Elizabeth R ER Hakala Kevin K Cates Courtney A CA Weintraub Susan T ST de Castro Brás Lisandra E LE

Proteomics. Clinical applications 20151217 1

<h4>Purpose</h4>Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. Of the MMPs, MMP-9 has the strongest link to the development of cardiac dysfunction. Aging associates with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged animals.<h4>Experimental design</h4>We used male and female middle-aged (10- to16-month old) and old (20- to 24-month old) wil ...[more]

PMID: 26415707

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Remodeling of the cardiac extracellular matrix proteome during chronological and pathological aging

Project description:Impaired extracellular matrix (ECM) remodeling is a hallmark of many chronic inflammatory disorders that can lead to cellular dysfunction, aging, and disease progression. The ECM of the aged heart and its effects on cardiac cells during chronological and pathological aging are relatively poorly understood in several speciesacross species. Here, we used mass spectrometry-based proteomics to quantitatively characterize age-related remodeling of the left ventricle (LV) of mice and humans during chronological and pathological (Hutchinson-Gilford progeria syndrome (HGPS)) aging. Of the approximately 300 ECM proteins quantified, we identified 13 proteins that were increased, including lactadherin (MFGE8), collagen VI 6 (COL6A6), vitronectin (VTN) and immunoglobulin heavy constant mu (IGHM), whereas fibulin-5 (FBLN5) was decreased in most of the data sets analyzed. We show that lactadherin accumulates with age in large cardiac blood vessels and when immobilized, triggers phosphorylation of several phosphosites of GSK3B, MAPK isoforms 1, 3, and 14, and MTOR kinases in aortic endothelial cells (ECs). In addition, immobilized lactadherin increased the expression of pro-inflammatory markers associated with an aging phenotype. These results extend our knowledge of the LV proteome remodeling induced by chronological and pathological aging in different species (mouse and human). The lactadherin-triggered changes in the proteome and phosphoproteome of ECs suggest a straight link between ECM component remodeling and the aging process of ECs.

2024-01-08 | PXD040234 | Pride

Remodeling of the cardiac extracellular matrix proteome during chronological and pathological aging

Project description:Impaired extracellular matrix (ECM) remodeling is a hallmark of many chronic inflammatory disorders that can lead to cellular dysfunction, aging, and disease progression. The ECM of the aged heart and its effects on cardiac cells during chronological and pathological aging are poorly understood across species. Here, we used mass spectrometry-based proteomics to quantitatively characterize age-related remodeling of the left ventricle (LV) of mice and humans during chronological and pathological (Hutchinson-Gilford progeria syndrome (HGPS)) aging. Of the approximately 300 ECM proteins quantified, we identified 13 proteins that were increased, including lactadherin (MFGE8), collagen VI 6 (COL6A6), vitronectin (VTN) and immunoglobulin heavy constant mu (IGHM), whereas fibulin-5 (FBLN5) was decreased in most of the data sets analyzed. We show that lactadherin accumulates with age in large cardiac blood vessels and when immobilized, triggers phosphorylation of several phosphosites of GSK3B, MAPK isoforms 1, 3, and 14, and MTOR kinases in aortic endothelial cells (ECs). In addition, immobilized lactadherin increased the expression of pro-inflammatory markers associated with an aging phenotype. These results extend our knowledge of the LV proteome remodeling induced by chronological and pathological aging in different species (mouse and human). The lactadherin-triggered changes in the proteome and phosphoproteome of ECs suggest a straight link between ECM component remodeling and the aging process of ECs.

2024-01-08 | PXD039548 | Pride

Extracellular Matrix Proteolysis by MT1-MMP is Associated with Influenza-Related Mortality

Project description:The balance between protecting tissue integrity and efficient immune response is critical for host survival. Here we investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection using a combined genomic and proteomic approach. We followed the transcriptional dynamics and ECM- related responses in a mouse model of influenza virus infection, integrated with whole tissue imaging and functional assays. Our study identifies MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza virus infection. We show that selective inhibition of MT1-MMP-driven ECM proteolysis protects the tissue from infection-related structural and compositional damage. Inhibition of MT1-MMP did not significantly alter the immune response or cytokine expression, indicating its dominant role in ECM remodeling. We demonstrate that the available treatment for influenza virus (Tamiflu/ Oseltamivir) does not prevent lung ECM damage and is less effective than anti-MT1-MMP treatment in influenza virus and Streptococcus pneumoniae coinfection paradigms. Importantly, combination therapy of Tamiflu with anti-MT1-MMP shows a strong synergistic effect and results in complete recovery in mice. This study highlights the importance of tissue tolerance agents for surviving infectious diseases, and the potential of such host-pathogen therapy combination for respiratory infections.

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Expression data from MMP-8 wild type and KO mice with or without arthritis

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Cathepsin A contributes to left ventricular remodeling by degrading the antioxidant enzyme extracellular superoxide dismutase

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Project description:Aging is associated with extensive remodeling of the heart, including basement membrane (BM) components that surround cardiomyocytes. Remodeling is thought to impair cardiac mechanotransduction, but the contribution of specific BM components to age-related lateral communication between cardiomyocytes is unclear. Using a genetically tractable, rapidly aging model with sufficient cardiac genetic homology and morphology, e.g. Drosophila melanogaster, we observed differential regulation of BM collagens between laboratory strains, correlating with changes in muscle physiology leading to cardiac dysfunction. Therefore, we sought to understand the extent to which BM proteins modulate contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin, Laminin A, and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression correlated with an overall preservation of contractile velocity with age and extension of organismal lifespan. Global heterozygous knockdown confirmed these data, which provides new evidence of a direct link between BM homeostasis, contractility, and maintenance of lifespan.

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