Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction

Potere, Nicola; Buono, Marco Giuseppe Del; Niccoli, Giampaolo; Crea, Filippo; Toldo, Stefano; Abbate, Antonio

doi:10.3390/ijms20030544

Cited by 26 publications

(30 citation statements)

References 110 publications

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“…One of the fragments of the cleaved RCL is inserted into the central beta-sheet of A1AT in both pathways, whereas the other fragment (36-aa) is released into the solvent. Notably, the 36-aa fragment is produced as a result of proteolytic cleavage by several serine proteases and possesses physiologic functions ( Blaurock et al, 2016 ; Potere et al, 2019 ; Risor et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Azouz

Klingler

Callahan

et al. 2020

Preprint

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The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-CoV, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an approach toward preventing transmission of coronaviruses. Herein, we developed an in vitro system to measure TMPRSS2 activity and tested the inhibition of TMPRSS2 by several synthetic and natural protease inhibitors. Camostat mesylate and bromhexine hydrochloride (BHH) inhibited TMPRSS2 proteolytic function. In addition, we identified the small molecule 4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF) and the human, anti-inflammatory protein alpha 1 antitrypsin (A1AT) as inhibitors of TMPRSS2. AEBSF and A1AT inhibited TMPRSS2 activity in a dose-dependent manner. AEBSF and A1AT inhibited TMPRSS2 in the same range of concentrations (100-0.1 μM). We suggest that treatment with these inhibitors, particularly A1AT, which is an FDA-approved drug, might be effective in limiting SARS-CoV and SARS-CoV2 transmissibility and as a COVID-19 treatment.

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Section: Discussionmentioning

confidence: 99%

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Azouz

Klingler

Callahan

et al. 2020

Preprint

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“…The endocytic function and signaling properties confer a major role to LRP1 in the pathophysiology of numerous diseases such as hepatic steatosis, kidney fibrosis, acute respiratory distress syndrome (ARDS), Alzheimer's disease (AD) and atherosclerosis (23). In addition, recent evidences showed that LRP1 is implicated in the pathophysiological mechanisms underlying AMI, IRI and adverse LV remodeling (20, 21).…”

Section: Low-density Lipoprotein Receptor-related Protein 1 (Lrp1): Gmentioning

confidence: 99%

“…LRP1 initiates signaling by direct ligand binding or, through its co-receptors, transactivates signal pathways. Although the exact mechanisms have been partly elucidated, the tyrosine phosphorylation at the NPxY motifs is necessary for LRP1-mediated signal transduction (21, 23, 27).…”

Section: Low-density Lipoprotein Receptor-related Protein 1 (Lrp1): Gmentioning

confidence: 99%

“…Among these, the multiligand, multifunctional and ubiquitous receptor, low-density lipoprotein receptor related protein-1 (LRP1), has emerged as a modulator of tissue inflammation and repair in several organs including the brain, lung, kidney and vasculature (19). Interestingly, recent research demonstrated that LRP1 also plays a major role in AMI (20, 21).…”

Section: Introductionmentioning

confidence: 99%

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

Potere

Buono

Mauro

et al. 2019

Front. Cardiovasc. Med.

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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.

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“…Finally, the potentiation of cardiomyocyte survival should be considered as a valuable alternative to be coopted in the treatment of MIRS. An interesting approach is the modulation of the low-density lipoprotein receptor-related protein 1 (LRP1), which is able to both downregulate the NF-κB-related inflammation during MIRS and enhance cardiomyocyte survival through the activation of the PI3K/Akt and ERK1/2 pathways in such cells, as thoroughly reviewed in [115]. As an example of this approach, a clinical trial using plasma-derived alpha-1 antitrypsin, an agonist of the LRP1 receptor, showed shorter time-to-peak creatine kinase myocardial band (CK-MB) values [116] in relation to a significant reduction on CRP [117] (Table 1).…”

Section: Immunoregulation As a Modern Alternative To Immunosuppressionmentioning

confidence: 99%

Ischemia/Reperfusion Injury: Pathophysiology, Current Clinical Management, and Potential Preventive Approaches

Sánchez-Hernández

Torres-Alarcón

González-Cortés

et al. 2020

Mediators of Inflammation

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Myocardial ischemia reperfusion syndrome is a complex entity where many inflammatory mediators play different roles, both to enhance myocardial infarction-derived damage and to heal injury. In such a setting, the establishment of an effective therapy to treat this condition has been elusive, perhaps because the experimental treatments have been conceived to block just one of the many pathogenic pathways of the disease, or because they thwart the tissue-repairing phase of the syndrome. Either way, we think that a discussion about the pathophysiology of the disease and the mechanisms of action of some drugs may shed some clarity on the topic.

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Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction

Cited by 26 publications

References 110 publications

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

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

Ischemia/Reperfusion Injury: Pathophysiology, Current Clinical Management, and Potential Preventive Approaches

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