Recurrent Exposure to Subclinical Lipopolysaccharide Increases Mortality and Induces Cardiac Fibrosis in Mice
Open Access
- 9 April 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (4), e61057
- https://doi.org/10.1371/journal.pone.0061057
Abstract
Background Circulating subclinical lipopolysaccharide (LPS) occurs in health and disease. Ingesting high fatty meals increases LPS that cause metabolic endotoxemia. Subclinical LPS in periodontal disease may impair endothelial function. The heart may be targeted as cardiac cells express TLR4, the LPS receptor. It was hypothesized that recurrent exposure to subclinical LPS increases mortality and causes cardiac fibrosis. Methods C57Bl/6 mice were injected with intraperitoneal saline (control), low dose LPS (0.1 or 1 mg/kg), or moderate dose LPS (10 or 20 mg/kg), once a week for 3 months. Left ventricular (LV) function (echocardiography), hemodynamics (tail cuff pressure) and electrocardiograms (telemetry) were measured. Cardiac fibrosis was assessed by picrosirius red staining and LV expression of fibrosis related genes (QRT-PCR). Adult cardiac fibroblasts were isolated and exposed to LPS. Results LPS injections transiently increased heart rate and blood pressure (<6 hours) and mildly decreased LV function with full recovery by 24 hours. Mice tolerated weekly LPS for 2–3 months with no change in activity, appearance, appetite, weight, blood pressure, LV function, oximetry, or blood chemistries. Mortality increased after 60–90 days with moderate, but not low dose LPS. Arrhythmias occurred a few hours before death. LV collagen fraction area increased dose-dependently from 3.0±0.5% (SEM) in the saline control group, to 5.6±0.5% with low dose LPS and 9.7±0.9% with moderate dose LPS (P<0.05 moderate vs low dose LPS, and each LPS dose vs control). LPS increased LV expression of collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, periostin and IL-6 (P<0.05 moderate vs low dose LPS and vs control). LPS increased α-SMA immunostaining of myofibroblasts. LPS dose-dependently increased IL-6 in isolated adult cardiac fibroblasts. Conclusions Recurrent exposure to subclinical LPS increases mortality and induces cardiac fibrosis.Keywords
This publication has 39 references indexed in Scilit:
- Interleukin-6, its role in fibrosing conditionsCytokine & Growth Factor Reviews, 2012
- The Emerging Role of Innate Immunity in the Heart and Vascular SystemCirculation Research, 2011
- Smad3 Signaling Critically Regulates Fibroblast Phenotype and Function in Healing Myocardial InfarctionCirculation Research, 2010
- TLR4 Promotes Fibrosis but Attenuates Tubular Damage in Progressive Renal InjuryJournal of the American Society of Nephrology, 2010
- Interleukin 6 Mediates Myocardial Fibrosis, Concentric Hypertrophy, and Diastolic Dysfunction in RatsHypertension, 2010
- Resilience to Bacterial Infection: Difference between Species Could Be Due to Proteins in SerumThe Journal of Infectious Diseases, 2010
- Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in HumansDiabetes, 2009
- Increase in Plasma Endotoxin Concentrations and the Expression of Toll-Like Receptors and Suppressor of Cytokine Signaling-3 in Mononuclear Cells After a High-Fat, High-Carbohydrate MealDiabetes Care, 2009
- Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular RemodelingCirculation Research, 2007
- Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in miceProceedings of the National Academy of Sciences of the United States of America, 2006