Apo AI Nanoparticles Delivered Post Myocardial Infarction Moderate Inflammation
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:127 |
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| Enthalten in: |
Circulation research - 127(2020), 11 vom: 06. Nov., Seite 1422-1436 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Richart, Adele L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.05.2021 Date Revised 24.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1161/CIRCRESAHA.120.316848 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315228636 |
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| 245 | 1 | 0 | |a Apo AI Nanoparticles Delivered Post Myocardial Infarction Moderate Inflammation |
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| 500 | |a Date Completed 24.05.2021 | ||
| 500 | |a Date Revised 24.05.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: To determine anti-inflammatory actions of n-apo AI (Apo AI nanoparticles) that contribute to cardiac tissue recovery after myocardial infarction | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Natoli, Alaina L |e verfasserin |4 aut | |
| 700 | 1 | |a Heywood, Sarah E |e verfasserin |4 aut | |
| 700 | 1 | |a Siebel, Andrew L |e verfasserin |4 aut | |
| 700 | 1 | |a Lancaster, Graeme L |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Carey, Andrew L |e verfasserin |4 aut | |
| 700 | 1 | |a Drew, Brian G |e verfasserin |4 aut | |
| 700 | 1 | |a Didichenko, Svetlana A |e verfasserin |4 aut | |
| 700 | 1 | |a Navdaev, Alexei V |e verfasserin |4 aut | |
| 700 | 1 | |a Kingwell, Bronwyn A |e verfasserin |4 aut | |
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