It is becoming increasingly evident that myocardial inflammation represents a key regulator of post-MI remodelling, which directs specific actions on individual components in this setting, but which is thought to preferentially target the ECM [
36]. Indeed, we have previously reported that the GLP-1 mimetic, exendin-4, protects against adverse cardiac remodelling in both normoglycaemic and diabetic mice via specific actions on infiltrating inflammatory cells [
18,
37]. In this regard, whilst GLP-1(9–36) did not affect the marked myocardial infiltration of CD45
+ leukocytes associated with MI, increased numbers of F4/80
+ macrophages, which are particularly prevalent in the ischaemic heart [
18,
38], were normalised by GLP-1(9–36). This was associated with reduced expression of the pro-inflammatory cytokines, IL-1β, IL-6 and MCP-1, which are critical for fibroblast differentiation, although mRNA levels of TGF-β
3 which also upregulates MMP/TIMP expression, were unaltered [
34,
39]. Interestingly, complementary in vitro experiments performed using RAW264.7 murine macrophages revealed a clear potentiation of basal mRNA expression of macrophage response genes, which are known to regulate tissue remodelling and repair, in the presence of GLP-1(9–36) compared with exendin-4, which we have previously reported to modulate resident and secreted cytokine expression in bone marrow-derived cells under both normal and high glucose conditions [
18,
37,
40,
41]. Importantly, GLP-1(9–36) appeared to upregulate both pro-inflammatory (IL-1β, TNF-α, IL-6, IL-12, Arg1) and tissue protective cytokines (IL-10, Fizz1), in addition to TGF-β
3 which is a major driver of ECM remodelling [
38,
39], highlighting global activation of macrophage function. It should be noted that whilst the employed concentration of GLP-1(9–36) in these in vitro experiments was based on that used in previous studies, it is higher than circulating levels typically found in vivo [
24,
42,
43]. Nonetheless, taken together with the observation that MI-induced macrophage infiltration was almost completely prevented by GLP-1(9–36), these data strongly suggest that this purportedly inactive peptide exerts significant actions which are relevant to cardiac remodelling. Whilst these findings are consistent with a previous report of GLP-1(9–36)-mediated inhibition of chemokine-induced migration of human CD4-positive lymphocytes [
44], which is established as an early and critical step in atherogenesis, ours is the first study to specifically link an immunomodulatory effect of GLP-1(9–36) to cardioprotection. Although this apparent modulation of the myocardial inflammatory response by GLP-1(9–36) is most likely to impact upon ECM remodelling and thereby explain the observed preservation of cardiac function, it is also possible that reduced cardiac macrophage infiltration and associated changes in gene expression may also influence cardiomyocyte function due to modulation of established paracrine communication between these two cell populations [
45]. Interestingly, recent reports that increased mitochondrial ROS generation associated with both high glucose exposure in human endothelial cells and Alzheimer’s disease in mouse hippocampal tissue, is attenuated by GLP-1(9–36) [
21,
46,
47], suggest that such antioxidant actions of GLP-1(9–36) may underlie the observed attenuation of post-MI remodelling, specific components of which are known to be significantly influenced by ROS [
48].