Abstract
Purpose: Myocardial healing after infarction is hampered by reperfusion injury and ventricular remodeling, partly mediated by detrimental inflammatory responses. We hypothesized that modulation of the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), an amplifier of the innate inflammatory response, by the use of a small synthetic peptide, LR12, could improve myocardial injury in a rodent model of myocardial infarction (MI). Methods: For hemodynamic assessment, we used Wistar rats which underwent either permanent occlusion of the left coronary artery or transient ischemia for one hour followed by reperfusion. They were randomly assigned to receive LR12 or vehicle for 5 days. Cardiac function and dimensions were assessed at baseline through positron emission tomography (PET) imaging and 6 weeks after infarction by PET and conductance catheter. For biological investigations, we used male Balb/c mouse with permanent MI and infusion of LR12 or vehicle from 1 hour after MI to day 5. TREM-1, protease activity and others myocardial inflammatory mediators tissue expression were quantified by western-blot, Elisa, and qRT-PCR. Leukocytes populations were studied in heart and blood samples. Results: Following permanent ischemia, LR12 reduced ventricular remodeling, as assessed by a lesser increase of end-diastolic volume measured by PET, and improved the systolic function evaluated by conductance catheter derived load-independent parameters (ESPVR: 0.98±0.43 vs 1.45±0.49 mmHg.μL-1, p=0.04; PRSW: 55±23 vs 80±34 mmHg.μL-1, p=0.03). During transient ischemia, LR12 infusion just before and for 5 days after reperfusion also improved myocardial contractility (PRSW: 64±25 vs 96±26, p=0.02; ESPVR 1.00±0.30 vs 1.61±0.69, p=0.05). TREM-1 was expressed in myocardial tissue, especially in infarcted areas, as early as 6 hours after MI, peaking at 24h. LR12 administration modulated myocardial inflammatory response with a reduction of p38 and ERK1/2 phosphorylation, iNOS and Cox2 expression, while Akt, GSK3β and Socs3 were up-regulated. LR12 modulated the expression of many chemokines (IL-6, -13, -17, TNF-α, ICAM-1), and decreased protease activity in myocardial infarcted areas (MMP9/TIMP1). LR12 profoundly modified leukocytes populations, with an increased number of circulating and myocardial non classical monocytes (Gr1-low) and LT4 at 96h post MI. Conclusion: LR12, by inhibiting TREM-1, improves ventricular remodeling and myocardial contractility in various experimental models of myocardial infarction. These effects are mediated by a profound switch in leukocytes recruitment to the healing myocardium.
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