Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

Abstract

Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called "Evasins" have been shown to inhibit both CC and CXC chemokine-mediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin-4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 μg Evasin-3, 1 μg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post-infarction heart failure in mice.

Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction

“…Indeed, we did not notice any difficulty during injection of the cell aggregates during our experiments. In addition, injection volumes of 20–30 μl were used in previous studies with mouse models823, and our animal survival is not significantly different from that reported in the literature for the treatment with saline535455. Moreover, with saline, ACM-A and ACM treatments in 20 μl of injection volume, we did not observe any granuloma formation.…”

“…The sample size was chosen to ensure adequate power to detect the difference between the saline control and ACM-A groups56. In brief, we estimated that the saline group had a survival rate of ∼35% from pilot studies and the literature535455, the hypothetical survival rate of ACM-A from pilot studies was 80%, the probability of type I error (α)=0.05, the power (1− β )=0.8, and ratio of sample sizes is 1, which gives sample size required for each group to be at least 24. Mice were euthanized by CO 2 exposure at 28 days, and heart samples were harvested for further analyses.…”

Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

“…To this end, up-regulation of circulatory and cardiac chemokines has been considered as a vital mechanism in leukocyte recruitment, early vascular inflammation, and atherogenesis. For instance, selective inhibition of CC chemokines CCL5 with Evasin-4 effectively reduced cardiac injury/inflammation and improved survival [29]. In the present study, we observed significant increase of both CCL21 and CCR7 after AMI as compared with sham-operated mice.…”

Long-Term Immune Alterations Accompanying Chronic Posttraumatic Stress Disorder following Exposure to Suicide Bomb Terror Incidents during Childhood

“…RANTES is chemotactic for T cells, eosinophils, and basophils and plays a classical role in recruiting activated leukocytes into inflammatory sites, and has been implicated with a variety of chronic inflammatory disorders including progression of Alzheimer disease [25], and trafficking of dendritic cells across the blood-brain barrier in experimental autoimmune encephalomyelitis [26]. RANTES has been further demonstrated to play a role in the progression of atherosclerosis [27], and in the triggering and propagation of coronary myocardial events, and selective inhibition of RANTES with evasin-4 was shown to reduce cardiac injury/inflammation and improve survival [28]. More recently, there has been increasing recognition of the substantial contribution of low-grade inflammation and immune responses driven by neoantigens generated by oxidative stress and modulated by RANTES, in causing hypertension [29].…”