A Preclinical Translational Study of the Cardioprotective Effects of Plasma-Derived Alpha-1 Anti-trypsin in Acute Myocardial Infarction

Abstract

Plasma-derived AAT (Prolastin C) given as an adjunct to reperfusion powerfully limits the final infarct size across a wide range of experiments in the mouse reproducing clinically relevant scenarios, such as variable duration of ischemia, delay in administration in the drug, and a large therapeutic index.

Low-Density Lipoprotein Receptor–Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction

“…The cardioprotective effects of SP16 are consistent with the effects seen with plasma-derived AAT and AT III , and with recombinant human AAT 10 , 11 , 23 . We showed in 2011 that plasma-derived AAT inhibited induction of the NLRP3 inflammasome and ischemia–reperfusion cardiomyocyte death in vitro and in vivo (10) .…”

“… (11) showed that AT III , another member of the SERPIN family, markedly reduced infarct size, independent of its anticoagulant activity. More recently, using different recombinant fusion proteins of human AAT and fragment crystallizable region of immunoglobulin G, we showed that the cardioprotective effects of AAT were independent of its ability to inhibit elastase (23) . Collectively, the data show that distinct LRP1 agonists derived from SERPINs induce a similar cardioprotective effect, independent of their ability to inhibit the proteases.…”

Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing

“…The anti-inflammatory effect of AAT was confirmed by the significant reduction in both pro-inflammatory cytokines levels and leukocytes infiltrating the heart tissue after ischemia-reperfusion (120). Likewise, plasma-derived AAT considerably reduced the acute myocardial inflammatory injury after ischemia-reperfusion in the mouse leading to preservation of viable myocardium and systolic function, and the effects persisted across a wide range of experiments in the mouse reproducing clinical relevant scenarios, such as variable duration of ischemia (up to 75 min), delay in administration of the drug (up to 30 min), and a large therapeutic index (121). The protective effects of AAT have been demonstrated to be independent from its neutrophil elastase-inhibiting activity, as a recombinant protein composed of human AAT fused to the human immunoglobulin (Ig) G1 Fc fragment (rhAAT-Fc) inhibited the inflammatory injury following acute ischemia (124).…”

Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction

“…The binding of SERPINs to LRP1 was shown to induce a pro-survival signal in several experimental settings, though its effects in a myocardial ischemia-reperfusion model remained unexplained until recently. LRP1 non-selective stimulation by SERPINs, such as with plasma-derived AAT, A2MG, and AT III , or with recombinant human AAT, significantly limited IRI [95,96,97,98,99]. Plasma derived AAT considerably inhibited cardiomyocyte death in vitro and in vivo [95], and the effects persisted when a clinically relevant scenario, such as prolonged ischemia (up to 75 min), delayed the administration of the drug (up to 30 min), and a large therapeutic index, was modeled in mice [96].…”

“…LRP1 non-selective stimulation by SERPINs, such as with plasma-derived AAT, A2MG, and AT III , or with recombinant human AAT, significantly limited IRI [95,96,97,98,99]. Plasma derived AAT considerably inhibited cardiomyocyte death in vitro and in vivo [95], and the effects persisted when a clinically relevant scenario, such as prolonged ischemia (up to 75 min), delayed the administration of the drug (up to 30 min), and a large therapeutic index, was modeled in mice [96]. The use of different isoforms of recombinant fusion proteins composed of human AAT and Fc portion of IgGs, showed that the protective effects of AAT are independent from the inhibition of elastase activity [99].…”