Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs

Abstract

Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We have recently reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days (d) reperfusion period. We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner.Single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiment along with complementary murine MI studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin's mechanisms of action. We conclude that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving cardiac function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.

Agrin-Mediated Cardiac Regeneration: Some Open Questions

“…This means that the DGC could well be involved in the sequestration of phosphorylated YAP at the cytosolic side of sarcolemma but, although agrin can induce DGC disassembly when administered to postnatal heart, factors other than agrin (or complementary to it) could induce the DGC disassembly believed to be responsible for YAP release during development. What is certain is that administration of exogenous agrin promotes the activation of this specific CMs proliferation program in mouse and possibly in larger mammals, as proposed by Baehr et al in a very recent preprint manuscript (Baehr et al, 2019) reporting the regenerative effect of intracoronary injection of agrin into porcine models of myocardial infarction.…”

“…Therefore, it is not known (i) how crucial is the role of agrin at different stages of human cardiac development and/or cardiomyocyte proliferation, (ii) whether exogenous agrin can exert on human hearts the same effect observed in mice. In this respect, some encouraging preliminary results have been obtained also in piglets, a model of MI more closely related to human cardiac physiology [see the preprint by Baehr et al (2019)].…”

“…Both in mouse (Bassat et al, 2017) and porcine (Baehr et al, 2019) models of myocardial infarction (MI), recombinant agrin injected locally in the damaged heart seems to have an overall cardioprotective effect, with anti-inflammatory and angiogenic components to add to CM protection and (mild) proliferation induction. As the authors suggest, agrin could then enhance heart healing via a series of pleiotropic effects, but the hypothesis that agrin may act through a promiscuous rather than a specific mechanism bears important implications/repercussions when trying to envisage regenerative strategies.…”

“…As the authors suggest, agrin could then enhance heart healing via a series of pleiotropic effects, but the hypothesis that agrin may act through a promiscuous rather than a specific mechanism bears important implications/repercussions when trying to envisage regenerative strategies. As an example, administration of agrin has been shown to stimulate the production of blood vessels in both murine and porcine MI (myocardial infarction) models (Baehr et al, 2019), which draws an analogy with the recently discovered role of agrin in recruiting endothelial cells within tumors and its ability to overall promote tumor angiogenesis (Njah et al, 2019). Specifically, agrin has been found to act in endothelial cells (ECs) by an ECM stiffness based mechanism similar to that described in tumor cells, although the mechanotransduction axis would not involve the activation of YAP/TAZ but rather the stabilization of VEGFR2 (Vascular Endothelial Growth Factor Receptor 2), a master regulator of ECs migration, proliferation and angiogenesis.…”

“…The last frontier would be that of employing the very latest technologies that created an acellular cardiac patch composed of synthetic microparticles containing secreted cardiac regenerative factors embedded in a scaffold formed by decellularized myocardial ECM (Huang et al, 2020), to allow release of agrin in the absence of the complications associated with cellular components. However, it remains to be determined whether any of the above patches would allow for the necessary time-restricted controlled delivery of recombinant agrin to the damaged heart, and local injection might still be the preferential and more efficient mean of administration, as recently shown in pig models of MI (Baehr et al, 2019).…”