Abstract
BackgroundExposure to subclinical levels of lipopolysaccharide (LPS) occurs commonly and is seemingly well tolerated. However, recurrent LPS exposure induces cardiac fibrosis over 2 to 3 months in a murine model, not mediated by the renin-angiotensin system. Subclinical LPS induces cardiac fibrosis by unique mechanisms.MethodsIn C57/Bl6 mice, LPS (10 mg/kg) or saline (control) were injected intraperitoneally once a week for 1–4 weeks. Mice showed no signs of distress, change in activity, appetite, or weight loss. Mice were euthanized after 3 days, 1, 2, or 4 weeks to measure cardiac expression of fibrosis-related genes and potential mediators (measured by QRT-PCR), including micro-RNA (miR) and NADPH oxidase (NOX). Collagen fraction area of the left ventricle was measured with picrosirius red staining. Cardiac fibroblasts isolated from adult mouse hearts were incubated with 0, 0.1, 1.0 or 10 ng/ml LPS for 48 hours.ResultsCardiac miR expression profiling demonstrated decreased miR-29c after 3 and 7 days following LPS, which were confirmed by QRT-PCR. The earliest changes in fibrosis-related genes and mediators that occurred 3 days after LPS were increased cardiac expression of TIMP-1 and NOX-2 (but not of NOX-4). This persisted at 1 and 2 weeks, with additional increases in collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, TIMP2, and periostin. There was no change in TGF-β or connective tissue growth factor. Collagen fraction area of the left ventricle increased after 2 and 4 weeks of LPS. LPS decreased miR-29c and increased NOX-2 in isolated cardiac fibroblasts.ConclusionsRecurrent exposure to subclinical LPS induces cardiac fibrosis after 2–4 weeks. Early changes 3 days after LPS were decreased miR-29c and increased NOX2 and TIMP1, which persisted at 1 and 2 weeks, along with widespread activation of fibrosis-related genes. Decreased miR-29c and increased NOX2, which induce cardiac fibrosis in other conditions, may uniquely mediate LPS-induced cardiac fibrosis.
Highlights
Lipopolysaccharide (LPS) may circulate in the blood at subclinical levels and be a risk factor for cardiovascular disease. [1,2] Circulating LPS from bacteria entering from the gut causes metabolic endotoxemia, with low grade inflammation, insulin resistance and weight gain
8] These adverse effects develop insidiously with no change in activity, appetite, weight, blood chemistries, left ventricular size or systolic function [8]. This may be important since exposure to subclinical LPS is common and cardiac fibrosis increases left ventricular stiffness, which is associated with heart failure with preserved ejection fraction (HFpEF). [9] HFpEF is as common as heart failure with reduced ejection fraction and is associated with significant morbidity and mortality, [10] but with few effective therapies [11]
The time course for developing cardiac fibrosis was examined in four groups of C57Bl/6 mice injected with i.p. saline or LPS 10 mg/kg/week for 1, 2, or 4 weeks
Summary
Lipopolysaccharide (LPS) may circulate in the blood at subclinical levels and be a risk factor for cardiovascular disease. [1,2] Circulating LPS from bacteria entering from the gut causes metabolic endotoxemia, with low grade inflammation, insulin resistance and weight gain. 8] These adverse effects develop insidiously with no change in activity, appetite, weight, blood chemistries, left ventricular size or systolic function [8]. Recurrent exposure to subclinical LPS induces cardiac fibrosis and increases mortality after 2–3 months in a murine model. This may be important since exposure to subclinical LPS is common and cardiac fibrosis increases left ventricular stiffness, which is associated with heart failure with preserved ejection fraction (HFpEF). Recurrent LPS exposure induces cardiac fibrosis over 2 to 3 months in a murine model, not mediated by the reninangiotensin system.
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