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

Nicola Potere,Antonio Abbate,Stefano Toldo,Marco Giuseppe Del Buono,Adolfo Gabriele Mauro

doi:10.3389/fcvm.2019.00051

Abstract

Acute myocardial infarction (AMI) leads to myocardial cell death and ensuing sterile inflammatory response, which represents an attempt to clear cellular debris and promote cardiac repair. However, an overwhelming, unopposed or unresolved inflammatory response following AMI leads to further injury, worse remodeling and heart failure (HF). Additional therapies are therefore warranted to blunt the inflammatory response associated with ischemia and reperfusion and prevent long-term adverse events. Low-density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitous endocytic cell surface receptor with the ability to recognize a wide range of structurally and functionally diverse ligands. LRP1 transduces multiple intracellular signal pathways regulating the inflammatory reaction, tissue remodeling and cell survival after organ injury. In preclinical studies, activation of LRP1-mediated signaling in the heart with non-selective and selective LRP1 agonists is linked with a powerful cardioprotective effect, reducing infarct size and cardiac dysfunction after AMI. The data from early phase clinical studies with plasma-derived α1-antitrypsin (AAT), an endogenous LRP1 agonist, and SP16 peptide, a synthetic LRP1 agonist, support the translational value of LRP1 as a novel therapeutic target in AMI. In this review, we will summarize the cellular and molecular bases of LRP1 functions in modulating the inflammatory reaction and the reparative process after injury in various peripheral tissues, and discuss recent evidences implicating LRP1 in myocardial inflammation and infarct healing.

Highlights

Despite therapeutic advances, acute myocardial infarction (AMI) remains the most common cause of heart failure (HF) worldwide and is associated with an unacceptable high rate of morbidity and mortality [1] Acute myocardial infarction (AMI) is often the result of an abrupt destabilization of a coronary atherosclerotic plaque with superimposed thrombosis that leads to prolonged perturbation of oxygen delivery to the heart, causing myocardial cell death [2]
We summarize some cellular and molecular aspects of lipoprotein receptor-related protein 1 (LRP1) endocytic/signaling functions in orchestrating the inflammatory response and in balancing tissue repair, and discuss the role of LRP1 in the pathobiology of ischemiareperfusion injury (IRI) and infarct healing
The ability of LRP1 to bind proteins released in the earliest stages of injury and to induce c-Jun phosphorylation and Akt-ERK1/2 activation supports a model in which LRP1, on the one hand, functions as an early injury detector and, on the other, facilitates repair and survival of injured cells

Summary

INTRODUCTION

Acute myocardial infarction (AMI) remains the most common cause of heart failure (HF) worldwide and is associated with an unacceptable high rate of morbidity and mortality [1] AMI is often the result of an abrupt destabilization of a coronary atherosclerotic plaque with superimposed thrombosis that leads to prolonged perturbation of oxygen delivery to the heart, causing myocardial cell death [2]. The ability of LRP1 to bind proteins released in the earliest stages of injury and to induce c-Jun phosphorylation and Akt-ERK1/2 activation supports a model in which LRP1, on the one hand, functions as an early injury detector and, on the other, facilitates repair and survival of injured cells These experimental evidences allow one to speculate that activation through LRP1 agonists of LRP1mediated signaling following tissue injury represents a key mechanism promoting resolution of the inflammatory response and formation of a functional scar, while enhancing survival of the damaged yet salvageable cells. Further research is warranted to better elucidate the cellular and molecular mechanisms driving LRP1-mediated infarct-sparing effect, including conditional cell-specific LRP1 knockout, to determine the cell-specific role of LRP1 signaling in AMI, and testing the effectiveness of LRP1 agonism in the presence of different comorbidities

CONCLUSION

Findings

Methods