Abstract
Cardioprotection refers to a strategy aimed at enhancing survival pathways in the injured yet salvageable myocardium following ischemia-reperfusion. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can be targeted following reperfusion, to induce a cardioprotective signaling through the activation of the reperfusion injury salvage kinase (RISK) pathway. The data from preclinical studies with non-selective and selective LRP1 agonists are promising, showing a large therapeutic window for intervention to reduce infarct size after ischemia-reperfusion. A pilot clinical trial with plasma derived α1-antitrypsin (AAT), a naturally occurring LRP1 agonist, supports the translational value of LRP1 as a novel therapeutic target for cardioprotection. A phase I study with a selective LRP1 agonist has been completed showing no toxicity. These findings may open the way to early phase clinical studies with pharmacologic LRP1 activation in patients with acute myocardial infarction (AMI).
Highlights
Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality world-wide [1]
Ischemia-reperfusion injury (IRI) refers to the phenomenon by which the injured yet still viable myocardium, which is in a delicate death–survival balance, is injured by the re-establishment of blood flow and the re-oxygenation of the ischemic myocardium, which is only incompletely salvaged by reperfusion [4]
A single intravenous administration of 60 mg/kg as α1-antitripsin (AAT) within 12 hours from admission showed a favorable safety profile, and, when compared to a historical placebo-treated group from a parallel clinical trial, the plasma derived AAT was associated with a blunted acute inflammatory response as indicated by lower C reactive protein (CRP) levels [104] and reduced estimated infarct size, measured as the area under the curve for creatine kinase-myocardial band (CK-MB) [105]
Summary
Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality world-wide [1]. The activation of the Akt and/or ERK1/2 kinase cascades results in (1) the indirect inhibition of apoptosis, by the deactivation of key pro-apoptotic proteins preventing cytochrome c release from the mitochondria [24,25,26]; (2) the inhibition of mPTP opening (leading to abolition of mitochondrial functions and myocyte necrosis) and the activation of the endothelial nitric oxide synthase (eNOS) [27,28]; (3) the phosphorylation of factors involved in the regulation of gene expression [29,30,31]; (4) and the direct inhibition of apoptosis, by inactivating caspase-3 and -9 [32,33]. Certain ligands (e.g., SERPINs, tissue-type plasminogen activator -tPA-) function as LRP1 agonists and stimulate LRP1 direct signaling or transactivate signal pathways through LRP1 co-receptors [40,45]
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