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Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion
1University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6.
Abstract:
Macrophages are found in the heart as part of the inflammatory response. To determine whether macrophages could contribute to myocardial dysfunction, rat ventricular myocytes were isolated and cocultured with elicited peritoneal macrophages in media containing tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, or endotoxin for 4 h. Cardiac myocytes were electrically stimulated, and fractional shortening was determined using videomicroscopy. When myocytes alone or myocytes in coculture with macrophages separated by a membrane were challenged with TNF-alpha, lipopolysaccharide, or IL-1, fractional shortening did not decrease. When macrophages were allowed to contact myocytes, fractional shortening decreased from 20. 1 +/- 0.9% in unchallenged macrophage-myocyte cocultures to 15.5 +/- 0.9, 16.3 +/- 0.8, and 15.8 +/- 0.6% when challenged for 4 h with TNF-alpha, endotoxin, or IL-1beta, respectively (P < 0.05). Myocytes had a mean adherence of 4.2 +/- 0.2 macrophages after TNF-alpha challenge compared with 2.6 +/- 0.3 for controls (P < 0.05). The number of adherent macrophages was associated with the decrease in fractional shortening. Anti-intercellular adhesion molecule-1 (ICAM-1) reduced macrophage adherence and prevented the decrease in fractional shortening. This decrease was also prevented by desferoxamine, superoxide dismutase, and nitro-L-arginine methyl ester. This suggests that activated macrophages adhere to myocytes via ICAM-1, and adherent macrophages decrease their contractile function via TNF-alpha, oxygen free radicals, and nitric oxide.
Insights
Activated macrophages adhering to heart cells reduce their function. This cardiac dysfunction is mediated by intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha (TNF-alpha), free radicals, and nitric oxide.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Physiology
Background:
- Macrophages are key immune cells involved in cardiac inflammatory responses.
- Understanding macrophage interactions with cardiomyocytes is crucial for addressing myocardial dysfunction.
Purpose of the Study:
- To investigate the direct impact of activated macrophages on cardiomyocyte contractile function.
- To elucidate the molecular mechanisms underlying macrophage-induced myocardial dysfunction.
Main Methods:
- Rat ventricular myocytes were co-cultured with elicited peritoneal macrophages.
- Cardiac myocyte function (fractional shortening) was assessed using videomicroscopy under various inflammatory conditions.
- Macrophage adherence to myocytes was quantified, and the role of ICAM-1 was examined using anti-ICAM-1 antibodies.
- The involvement of TNF-alpha, oxygen free radicals, and nitric oxide was investigated using specific inhibitors and scavengers.
Main Results:
- Direct contact between activated macrophages and cardiomyocytes significantly reduced myocyte fractional shortening.
- Macrophage adherence to myocytes increased upon inflammatory challenge (TNF-alpha, endotoxin, IL-1beta) and correlated with decreased contractility.
- Inhibition of ICAM-1, TNF-alpha, oxygen free radicals, or nitric oxide prevented the macrophage-induced decline in myocyte function.
Conclusions:
- Activated macrophages adhere to cardiomyocytes via ICAM-1, leading to impaired cardiac contractility.
- The detrimental effects on cardiomyocyte function are mediated by TNF-alpha, oxygen free radicals, and nitric oxide.
- Targeting macrophage-myocyte interactions presents a potential therapeutic strategy for inflammatory heart conditions.