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Role of cardiac mast cells in complement C5a-induced myocardial ischemia
B R Ito1, R L Engler, U del Balzo
1Department of Medicine, University of California, San Diego 92103.
Insights
Complement component C5a induces myocardial ischemia via mast cell activation and mediator release. Inhibiting mast cell degranulation significantly reduces C5a-induced cardiac dysfunction, highlighting mast cells as key players in this inflammatory response.
Area of Science:
- Cardiovascular Physiology
- Immunology
- Inflammation Biology
Background:
- Activated complement component C5a is known to induce myocardial ischemia.
- This effect is mediated by thromboxane A2 and leukotrienes, but blood cells are not involved, suggesting a cardiac-resident cell.
- Mast cells are implicated as potential mediators in C5a-induced cardiovascular responses.
Purpose of the Study:
- To investigate if cardiac mast cell activation accompanies C5a response.
- To determine if inhibiting mast cell degranulation affects C5a-induced myocardial ischemia.
- To assess the role of histamine release in C5a-induced myocardial ischemia.
Main Methods:
- Open-chest pig model with constant pressure perfusion of the left anterior descending coronary artery.
- Measurement of coronary blood flow (CBF) and regional function (percent segment shortening, %SS).
- Analysis of coronary venous plasma for thromboxane B2 (TxB2) and histamine levels; administration of lodoxamide to inhibit mast cell degranulation.
Main Results:
- Intracoronary C5a infusion decreased CBF by 45% and %SS by 65%, with increased TxB2 and histamine.
- Mast cell inhibition with lodoxamide significantly attenuated the C5a-induced decrease in CBF (14% vs. 53%) and %SS (10% vs. 38%).
- Lodoxamide also reduced C5a-induced increases in coronary venous histamine and TxB2, while histamine receptor blockade had no effect.
Conclusions:
- Cardiac mast cell activation is a key component of the C5a-induced myocardial ischemia.
- Inhibition of mast cell degranulation effectively mitigates C5a-mediated cardiac dysfunction.
- Histamine release is not the primary mediator of C5a-induced myocardial ischemia, suggesting other mast cell-derived factors are involved.
Abstract:
Activated complement component C5a causes myocardial ischemia mediated by thromboxane (Tx) A2 and leukotrienes C4/D4. Blood cells are not involved in either the mediator release or the myocardial effects of C5a, suggesting that a C5a-sensitive, cardiac resident inflammatory cell is responsible. The goals of this study were to determine whether 1) cardiac mast cell activation accompanies the C5a response, 2) inhibition of mast cell degranulation inhibits the response, and 3) histamine release plays a role in the C5a-induced myocardial ischemia. The left anterior descending coronary artery (LAD) of open-chest pigs (n = 13) was perfused with arterial blood at constant pressure (95 mmHg). Coronary blood flow (CBF) was measured (in-line flowmeter) and regional function [percent segment shortening (%SS)] determined with sonomicrometry. A coronary vein was cannulated for measurement of plasma TxB2 and histamine (a marker of mast cell degranulation). Intracoronary C5a (500 ng) decreased coronary blood flow (45% of preinfusion levels) and LAD %SS (65% of preinfusion) and was accompanied by increases in coronary venous TxB2 (delta 63.3 ng/ml) and histamine (delta 200 nM). Mast cell inhibition with lodoxamide (2 mg/kg iv, n = 8) attenuated the C5a-induced fall in CBF (14 vs. 53% decrease, P < 0.01) and %SS (10 vs. 38% decrease, P < 0.01) and also reduced the C5a-induced increase in both coronary venous histamine (delta 26 vs. 278 nM, P < 0.05) and TxB2 (delta 0.34 vs. 63.3 ng/ml, P < 0.01). However, histamine H1 (pyrilamine) and H2 (ranitidine) receptor blockade had no effect on the C5a-induced fall in CBF or LAD %SS.(ABSTRACT TRUNCATED AT 250 WORDS)