Abstract 12412: Inhibition of P2X7 Receptor Signaling Promotes Adverse Cardiac Remodeling after Myocardial Infarction through Enhanced Cardiac Fibroblast Migration
Background: P2X7 receptor (P2X7R) is a member of the P2X receptor family which is comprised of ligand-gated ion channels. P2X7R is mainly expressed on macrophages and monocytes and activated by ATP and cathelicidin antimicrobial peptide (CAMP). ATP/P2X7R has been thought to be involved in proinflammatory signaling, because it activates cryopyrin/apotosis speck-like protein containing a caspase recruitment domain (ASC) inflammasome and elicits increased caspase-1 activity and IL-1β expression in acute inflammation. However, the long-term effects of P2X7R signaling inhibition on cardiac remodeling after myocardial infarction (MI) remain to be elucidated.
Objective: To identify the physiological role of P2X7R signaling in progression of cardiac remodeling after MI.
Methods and Results: MI was generated by ligating the left coronary artery in C57BL/6 mice. P2X7R expression was upregulated in hearts from day 4 to day 14 (day 4; 25.7±7.4, day 14; 7.3±2.0 fold increase vs control, n=5-6, day 4: p≤0.01). To determine the functional role of P2X7R in heart, we generated MI in control or P2X7R knockout (KO) mice. Importantly, deficiency of P2X7R aggravated fibrosis (control; 32.4±11.0%, P2X7R KO; 57.4±9.6%, n=6-7, p≤0.01) and cardiac dysfunction (fractional shortening: control; 37.6±8.3%, P2X7R KO; 24.8±11.4%, n=6-7, p≤0.05) at day 14 after MI. To elucidate the underlying mechanism of protective effect caused by P2X7R after MI, we investigated the inflammasome activation in P2X7R null mice. However, there were no differences in ASC expression, caspase-1 activity and IL-1β expression after MI between control and P2X7R KO mice. On the other hand, we observed sustained upregulation of CAMP, a well-known agonist of P2X7R, in hearts after MI. In vitro experiments revealed that treatment with LL37, a human homologue of CAMP, decreased migration distances of cardiac fibroblasts assessed by wound healing assay. Moreover, ablation of P2X7R abrogated LL37-mediated inhibition of cardiac fibroblast migration.
Conclusion: CAMP-P2X7R signaling plays cardioprotective roles in the suppression of cardiac remodeling after MI via inhibition of cardiac fibroblast migration. Thus, CAMP-P2X7R signaling could be a novel therapeutic target for heart failure after MI.
- © 2013 by American Heart Association, Inc.