Dataset Information

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

ABSTRACT: Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE(-/-) mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)-targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI.

SUBMITTER: Sager HB

PROVIDER: S-EPMC5125383 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

Sager Hendrik B HB Dutta Partha P Dahlman James E JE Hulsmans Maarten M Courties Gabriel G Sun Yuan Y Heidt Timo T Vinegoni Claudio C Borodovsky Anna A Fitzgerald Kevin K Wojtkiewicz Gregory R GR Iwamoto Yoshiko Y Tricot Benoit B Khan Omar F OF Kauffman Kevin J KJ Xing Yiping Y Shaw Taylor E TE Libby Peter P Langer Robert R Weissleder Ralph R Swirski Filip K FK Anderson Daniel G DG Nahrendorf Matthias M

Science translational medicine 20160601 342

Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE(-/-) mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively s ...[more]

PMID: 27280687

Similar Datasets

Project description:BackgroundPreclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Methods and resultsOverall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.ConclusionsThe presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:Ischemic heart diseases such as myocardial infarction (MI) are the largest contributors to cardiovascular disease worldwide. The resulting cardiac cell death impairs function of the heart and can lead to heart failure and death. Reperfusion of the ischemic tissue is necessary but causes damage to the surrounding tissue by reperfusion injury. Cortical bone stem cells (CBSCs) have been shown to increase pump function and decrease scar size in a large animal swine model of MI. To investigate the potential mechanism for these changes, we hypothesized that CBSCs were altering cardiac cell death after reperfusion. To test this, we performed TUNEL staining for apoptosis and antibody-based immunohistochemistry on tissue from Göttingen miniswine that underwent 90 min of lateral anterior descending coronary artery ischemia followed by 3 or 7 days of reperfusion to assess changes in cardiomyocyte and noncardiomyocyte cell death. Our findings indicate that although myocyte apoptosis is present 3 days after ischemia and is lower in CBSC-treated animals, myocyte apoptosis accounts for <2% of all apoptosis in the reperfused heart. In addition, nonmyocyte apoptosis trends toward decreased in CBSC-treated hearts, and although CBSCs increase macrophage and T-cell populations in the infarct region, the occurrence of apoptosis in CD45+ cells in the myocardium is not different between groups. From these data, we conclude that CBSCs may be influencing cardiomyocyte and noncardiomyocyte cell death and immune cell recruitment dynamics in the heart after MI, and these changes may account for some of the beneficial effects conferred by CBSC treatment.NEW & NOTEWORTHY The following research explores aspects of cell death and inflammation that have not been previously studied in a large animal model. In addition, apoptosis and cell death have not been studied in the context of cell therapy and myocardial infarction. In this article, we describe interactions between cell therapy and inflammation and the potential implications for cardiac wound healing.

Dataset Information

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

Publications

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets