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Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction.

ABSTRACT: Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger and regulatory receptor, inducing anti-inflammatory and prosurvival signals. Based on the known structure-activity of the LRP1 receptor binding site, the authors synthesized a small peptide (SP16). SP16 induced a >50% reduction in infarct size (p < 0.001) and preservation of left ventricular systolic function (p < 0.001), and treatment with an LRP1 blocking antibody eliminated the protective effects of SP16. In conclusion, LRP1 activation with SP16 given within 30 min of reperfusion during experimental acute myocardial infarction leads to a cardioprotective signal reducing infarct size and preservation of cardiac systolic function.

SUBMITTER: Toldo S

PROVIDER: S-EPMC6058925 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction.

Toldo Stefano S Austin Dana D Mauro Adolfo G AG Mezzaroma Eleonora E Van Tassell Benjamin W BW Marchetti Carlo C Carbone Salvatore S Mogelsvang Soren S Gelber Cohava C Abbate Antonio A

JACC. Basic to translational science 20171030 5

Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger and regulatory receptor, inducing anti-inflammatory and prosurvival signals. Based on the known structure-activity of the LRP1 receptor binding site, the authors synthesized a small peptide (SP16). SP16 induced a >50% reduction in infarct size (p < 0.001) and preservation of left ventricular systolic function (p < 0.001), and treatment with an LRP1 blocking antibody eliminated t ...[more]

PMID: 30062170

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Project description:Background Real-world data on low baseline low-density lipoprotein cholesterol (LDL-C) levels and long-term postdischarge cardiovascular outcomes in patients with acute coronary syndrome are limited. Methods and Results Of the 10 719 patients enrolled in the Korean registry of acute myocardial infarction between January 2004 and August 2014, we identified 5532 patients who were event free from death, recurrent myocardial infarction, or stroke during the in-hospital period after successful percutaneous coronary intervention. The co-primary outcomes were 3-point major adverse cardiovascular events (a composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death) and cardiovascular death at 5 years. Of 5532 patients with acute myocardial infarction (mean age, 62.1±12.8 years; 75.0% men), 446 cardiovascular deaths (8.1%) and 695 three-point major adverse cardiovascular events (12.6%) occurred at 5 years. In the continuous analysis of LDL-C, the risk of cardiovascular events increased steeply as LDL-C levels decreased from 100 mg/dL. For categorical analysis of LDL-C (<70, 70-99, and ≥100 mg/dL), as LDL-C levels decreased, clinical outcomes worsened (237/3759 [6.3%] in LDL-C ≥100 mg/dL versus 123/1291 [9.5%] in LDL-C 70-99 mg/dL versus 86/482 [17.8%] in LDL-C <70 mg/dL for cardiovascular death; P-trend<0.001; and 417/3759 [11.1%] in LDL-C ≥100 mg/dL versus 172/1291 [13.3%] in LDL-C 70-99 mg/dL versus 106/482 [22.2%] in LDL-C <70 mg/dL for 3-point major adverse cardiovascular event; P-trend<0.001). In a Cox time-to-event multivariable model with LDL-C levels ≥100 mg/dL as the reference, the baseline LDL-C level <70 mg/dL was independently associated with an increased incidence of cardiovascular death (adjusted hazard ratio, 1.68 [95% CI, 1.30-2.17]) and 3-point major adverse cardiovascular event (adjusted hazard ratio, 1.37 [95% CI, 1.10-1.71]). Conclusions In this Korean acute myocardial infarction registry, the baseline LDL-C level <70 mg/dL was significantly associated with an increased incidence of long-term cardiovascular events after discharge. (COREA [Cardiovascular Risk and Identification of Potential High-Risk Population]-Acute Myocardial Infarction Registry; NCT02806102). Registration URL: https://www.clinicaltrials.gov/; Unique identifier: NCT02806102.

Project description:AimHigh-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure.MethodsFive major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS.ResultsMultiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism.ConclusionsMinor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.

Dataset Information

Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction.

Publications

Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction.

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