Low-density lipoprotein receptor-related protein 1 as a therapeutic target in acute myocardial infarction: From mechanisms to clinical translation.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitously expressed, multifunctional membrane receptor that combines scavenger and signaling functions regulating, among others, lipid metabolism, inflammation and fibrosis pathways, cell survival, and extracellular matrix remodeling. In acute myocardial infarction (AMI), these integrated actions of LRP1 are highly relevant because myocardial salvage and infarct healing depend on tuned control of ischemia-reperfusion injury (IRI), innate immune activation, and reparative remodeling. Despite major advances in reperfusion strategies, additional therapies are needed to blunt excessive postischemic inflammation and improve short and long-term outcomes after AMI. In preclinical models of AMI, LRP1 agonism limits IRI by promoting cardiomyocyte survival and dampening inflammatory amplification; this is accompanied by smaller infarct size, improved systolic function, reduced leukocyte-driven tissue damage, resulting in improved infarct healing and protection from adverse ventricular remodeling. Early clinical translation studies evaluated pharmacologic activation of this pathway. Recent pilot studies in patients with ST-elevation AMI using plasma-derived α1 antitrypsin, an endogenous LRP1 agonist, and synthetic peptide 16, a synthetic LRP1-agonist peptide, indicate feasibility and short-term tolerability, with preliminary signals consistent with reduced inflammatory burden and enzymatic injury, requiring further evaluation in larger randomized controlled trials. In this review, we summarize the molecular and cellular basis of LRP1 functions in the regulation of postinfarction cardiac inflammation and repair. We also discuss emerging clinical evidence supporting LRP1 as a novel therapeutic target to reduce IRI and promote infarct healing in patients with AMI. SIGNIFICANCE STATEMENT: Despite modern reperfusion strategies, maladaptive postischemic inflammation remains a major driver of adverse remodeling and heart failure. Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional receptor that integrates scavenger and signaling functions to modulate ischemia-reperfusion injury (IRI), inflammatory amplification, and postinfarction repair. This review herein synthesizes emerging preclinical and clinical evidence supporting LRP1 agonism as a novel therapeutic target to limit IRI and promote infarct healing in patients with acute myocardial infarction.