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

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.

Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma

“…SIGLEC1 overexpression has been associated with poorer survival in several cancers 15 , 16 LRP1 (LDL Receptor Related Protein ) 3 LRP1 plays a significant role in the endocytosis of lipoproteins. LRP1 overexpression has been associated with invasion and migration of tumor cells 17 , 18 LOXL2 (Lysyl Oxidase Like 2) 5 LOXL2 is part of extracellular enzyme family which cross-links elastin and fibrillar collagen. LOXL2 overexpression has been associated with several cancers including breast, gastric, colon, esophageal and pancreatic cancer 19 SERPINE1 (Serpin Family E Member 1) 5 SERPINE1 is an inhibitor of urokinase and tissue plasminogen activator.…”

The Interplay of WNT and PPARγ Signaling in Vascular Calcification

“…This LRP1-WNT5a link was also evidenced in fibroblasts, where TGFβ treatment—a factor known to originate from the injured vessel wall—of LRP1-deficient fibroblasts did not induce WNT5a transcription and provoked a considerably lower protein induction than found in control fibroblasts [ 149 , 150 , 151 ]. Notably, TGFβ is also a well-known ligand for LRP1, where it plays a role in fibroblast activation and ECM synthesis [ 152 ]. Further, TGFβ promotes osteogenesis and migration of MSC, while also inducing osteochondrogenic effects on VSMC.…”

From the low-density lipoprotein receptor–related protein 1 to neuropathic pain: a potentially novel target

“…Lately, studies have focused on 1 specific novel target: the low-density lipoprotein receptor–related protein 1 (LRP-1). It is known that LRP-1 is highly involved in many inflammatory processes and diseases, including cancer, 120 kidney, lung, and heart diseases, 58 , 90 , 118 or atherosclerosis. 33 Evidence indicates that LRP-1 is not only modulating inflammation, but it also has an effect on learning, memory, and cognition processes and is involved in neurological disorders such as Alzheimer disease 39 , 84 and brain injury 33 and in pain.…”