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Measuring Pressure Volume Loops in the Mouse
Published on: May 2, 2016
Osteoglycin prevents the development of age-related diastolic dysfunction during pressure overload by reducing
Sophie Deckx1, Ward Heggermont2, Paolo Carai1
1Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, The Netherlands; Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Belgium.
Insights
Osteoglycin protects the heart against fibrosis and inflammation during aging and pressure overload. Its absence exacerbates cardiac dysfunction, highlighting its role in maintaining heart health.
Area of Science:
- Cardiovascular Biology
- Proteoglycan Research
- Aging and Heart Disease
Background:
- Osteoglycin (OGN) is a small leucine-rich proteoglycan involved in matrix homeostasis.
- Its role in hypertensive heart disease, aging, and cardiac remodeling is largely unknown.
- Angiotensin-II (Ang-II) infusion and aging are key factors in cardiac pathology.
Purpose of the Study:
- To investigate the role of osteoglycin in cardiac hypertrophy, fibrosis, and inflammation.
- To determine OGN's modulation of cardiac function during aging and hypertensive heart disease.
- To explore OGN's impact on macrophages and cardiac fibroblasts.
Main Methods:
- Utilized Angiotensin-II infusion in osteoglycin-null (OGN-/-) and wild-type (WT) mice.
- Assessed cardiac structure and function using magnetic resonance imaging (MRI).
- Performed in vitro studies on bone marrow-derived macrophages and human cardiac fibroblasts.
Main Results:
- Ang-II infusion increased cardiac OGN expression, inflammation, and extracellular matrix deposition.
- Aging decreased cardiac OGN levels; OGN absence exacerbated Ang-II-induced fibrosis and inflammation, leading to diastolic dysfunction.
- OGN deficiency in macrophages increased ICAM-1, IL-1β, and MCP-1 levels upon Ang-II stimulation.
- OGN inhibited cardiac fibroblast proliferation and TGF-β-induced collagen gene expression.
- OGN expression correlated inversely with TGF-β and collagen content in aortic stenosis patients.
Conclusions:
- Osteoglycin expression increases with cardiac pressure overload.
- Absence of OGN worsens cardiac inflammation and fibrosis, contributing to diastolic dysfunction.
- OGN plays a protective role in the aging and hypertensive heart, potentially through anti-inflammatory and anti-fibrotic mechanisms.
Abstract:
The small leucine-rich proteoglycan osteoglycin has been implicated in matrix homeostasis in different organs, including the ischemic heart. However, whether osteoglycin modulates cardiac hypertrophy, fibrosis or inflammation in hypertensive heart disease and during aging remains unknown. Angiotensin-II-induced pressure overload increases cardiac osteoglycin expression, concomitant with the onset of inflammation and extracellular matrix deposition. Interestingly aging led to decreased cardiac levels of osteoglycin, yet absence of osteoglycin did not affect organ structure or cardiac function up to the age of 18months. However, Angiotensin-II infusion in combination with aging resulted in exaggerated cardiac fibrosis and inflammation in the osteoglycin null mice as compared to wild-type mice, resulting in increased diastolic dysfunction as determined by magnetic resonance imaging. In vitro, stimulation of bone marrow derived macrophages from osteoglycin null mice with Angiotensin-II resulted in significantly higher levels of ICAM-1 as well as pro-inflammatory cytokines and chemokines IL-1β and MCP-1 as compared to WT cells. Further, stimulation of human cardiac fibroblasts with osteoglycin reduced cell proliferation and inhibited TGF-β induced collagen gene expression. In mouse cardiac tissue, osteoglycin expression inversely correlated with TGF-β expression and in cardiac biopsies of aortic stenosis patients, osteoglycin expression is significantly higher than in control biopsies. Interestingly, osteoglycin levels were higher in patients with less severe myocardial fibrosis and overall in the aortic stenosis patients osteoglycin levels negatively correlated with collagen content in the myocardium. In conclusion, osteoglycin expression is increased in the heart in response to pressure overload and its absence results in increased cardiac inflammation and fibrosis resulting in increased diastolic dysfunction.
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