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1.
Circ Res ; 127(11): 1422-1436, 2020 11 06.
Article in English | MEDLINE | ID: mdl-32951519

ABSTRACT

RATIONALE: Decades of research have examined immune-modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure but have failed to translate to clinical benefit. OBJECTIVE: To determine anti-inflammatory actions of n-apo AI (Apo AI nanoparticles) that contribute to cardiac tissue recovery after myocardial infarction. METHODS AND RESULTS: Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apo AI (CSL111, 80 mg/kg) delivered immediately after reperfusion reduced the systemic and cardiac inflammatory response. N-apo AI treatment lowered the number of circulating leukocytes by 30±7% and their recruitment into the ischemic heart by 25±10% (all P<5.0×10-2). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I, by 52±17% (P=1.01×10-2). N-apo AI reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60% to 80% and lowered surface expression of integrin CD11b on monocytes by 20±5% (all P<5.0×10-2). Fluorescently labeled n-apo AI entered the infarct and peri-infarct regions and colocalized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apo AI binds to neutrophils and monocytes, with preferential binding to the proinflammatory monocyte subtype and partially via SR-BI (scavenger receptor BI). In patients with type 2 diabetes, we also observed that intravenous infusion of the same n-apo AI (CSL111, 80 mg/kg) similarly reduced the level of circulating leukocytes by 12±5% (all P<5.0×10-2). CONCLUSIONS: A single intravenous bolus of n-apo AI delivered immediately post-myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apo AI and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Apolipoprotein A-I/administration & dosage , Inflammation/prevention & control , Leukocytes/drug effects , Myocardial Infarction/drug therapy , Nanoparticles , Administration, Intravenous , Adult , Animals , CD11b Antigen/metabolism , Cells, Cultured , Chemokines/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/immunology , Disease Models, Animal , Drug Administration Schedule , Humans , Inflammation/immunology , Inflammation/metabolism , Leukocytes/immunology , Leukocytes/metabolism , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Myocardial Infarction/immunology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Randomized Controlled Trials as Topic , Scavenger Receptors, Class B/genetics , Scavenger Receptors, Class B/metabolism , Troponin I/blood
2.
J Am Heart Assoc ; 8(11): e011792, 2019 06 04.
Article in English | MEDLINE | ID: mdl-31131674

ABSTRACT

Background Although acute coronary syndromes (ACS) are a major cause of morbidity and mortality, relationships with biologically active lipid species potentially associated with plaque disruption/erosion in the context of their lipoprotein carriers are indeterminate. The aim was to characterize lipid species within lipoprotein particles which differentiate ACS from stable coronary artery disease. Methods and Results Venous blood was obtained from 130 individuals with de novo presentation of an ACS (n=47) or stable coronary artery disease (n=83) before coronary catheterization. Lipidomic measurements (533 lipid species; liquid chromatography electrospray ionization/tandem mass spectrometry) were performed on whole plasma as well as 2 lipoprotein subfractions: apolipoprotein A1 (apolipoprotein A, high-density lipoprotein) and apolipoprotein B. Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein (high-density lipoprotein, 113 lipids; plasma, 73 lipids). Models including plasma lipid species alone improved discrimination between the stable and ACS groups by 0.16 (C-statistic) compared with conventional risk factors. Models utilizing lipid species either in plasma or within lipoprotein fractions had a similar ability to discriminate groups, though the C-statistic was highest for plasma lipid species (0.80; 95% CI, 0.75-0.86). Conclusions Multiple lysophospholipids, but not cholesterol, featured among the lipids which were present at low concentration within high-density lipoprotein of those presenting with ACS. Lipidomics, when applied to either whole plasma or lipoprotein fractions, was superior to conventional risk factors in discriminating ACS from stable coronary artery disease. These associative mechanistic insights elucidate potential new preventive, prognostic, and therapeutic avenues for ACS which require investigation in prospective analyses.


Subject(s)
Acute Coronary Syndrome/blood , Cholesterol/blood , Coronary Artery Disease/blood , Lipidomics , Lipoproteins, HDL/blood , Non-ST Elevated Myocardial Infarction/blood , Phospholipids/blood , ST Elevation Myocardial Infarction/blood , Acute Coronary Syndrome/diagnosis , Aged , Biomarkers/blood , Coronary Artery Disease/diagnosis , Cross-Sectional Studies , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Non-ST Elevated Myocardial Infarction/diagnosis , Predictive Value of Tests , ST Elevation Myocardial Infarction/diagnosis
3.
Sci Transl Med ; 9(411)2017 Oct 11.
Article in English | MEDLINE | ID: mdl-29021167

ABSTRACT

Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.


Subject(s)
Lipoproteins, HDL/therapeutic use , Myocardial Infarction/drug therapy , Animals , Glucose/metabolism , Male , Mice , Mice, Inbred C57BL , Myocardial Reperfusion Injury/drug therapy , Myocardium/metabolism , Myocardium/pathology , Signal Transduction/drug effects
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