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Phosphorylcholine Antibodies Preserve Cardiac Function and Reduce Infarct Size by Attenuating the Post-Ischemic Inflammatory Response.

ABSTRACT: Phosphorylcholine monoclonal immunoglobulin G antibody attenuates the immediate post-ischemic inflammatory response by reducing the proinflammatory chemokine (C-C motif) ligand 2 chemokine and circulating Ly-6C^hi monocytes. This subsequently enhances the post-ischemic repair process, resulting in limited adverse cardiac remodeling and preservation of cardiac function. Therefore, phosphorylcholine monoclonal immunoglobulin G antibody therapy may be a valid therapeutic approach against myocardial ischemia-reperfusion injury.

SUBMITTER: Pluijmert NJ

PROVIDER: S-EPMC7775955 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Phosphorylcholine Antibodies Preserve Cardiac Function and Reduce Infarct Size by Attenuating the Post-Ischemic Inflammatory Response.

Pluijmert Niek J NJ de Jong Rob C M RCM de Vries Margreet R MR Pettersson Knut K Atsma Douwe E DE Jukema J Wouter JW Quax Paul H A PHA

JACC. Basic to translational science 20201202 12

Phosphorylcholine monoclonal immunoglobulin G antibody attenuates the immediate post-ischemic inflammatory response by reducing the proinflammatory chemokine (C-C motif) ligand 2 chemokine and circulating Ly-6C<sup>hi</sup> monocytes. This subsequently enhances the post-ischemic repair process, resulting in limited adverse cardiac remodeling and preservation of cardiac function. Therefore, phosphorylcholine monoclonal immunoglobulin G antibody therapy may be a valid therapeutic approach against ...[more]

PMID: 33426378

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Project description:PurposePlasma membranes constitute a gathering point for lipids and signaling proteins. Lipids are known to regulate the location and activity of signaling proteins under physiological and pathophysiological conditions. Membrane lipid therapies (MLTs) that gradually modify lipid content of plasma membranes have been developed to treat chronic disease; however, no MLTs have been developed to treat acute conditions such as reperfusion injury following myocardial infarction (MI) and percutaneous coronary intervention (PCI). A fusogenic nanoliposome (FNL) that rapidly incorporates exogenous unsaturated lipids into endothelial cell (EC) membranes was developed to attenuate reperfusion-induced protein signaling. We hypothesized that administration of intracoronary (IC) FNL-MLT interferes with EC membrane protein signaling, leading to reduced microvascular dysfunction and infarct size (IS).MethodsUsing a myocardial ischemia/reperfusion swine model, the efficacy of FNL-MLT in reducing IS following a 60-min coronary artery occlusion was tested. Animals were randomized to receive IC Ringer's lactate solution with or without 10 mg/mL/min of FNLs for 10 min prior to reperfusion (n = 6 per group).ResultsThe IC FNL-MLT reduced IS (25.45 ± 16.4% vs. 49.7 ± 14.1%, P < 0.02) and enhanced regional myocardial blood flow (RMBF) in the ischemic zone at 15 min of reperfusion (2.13 ± 1.48 mL/min/g vs. 0.70 ± 0.43 mL/min/g, P < 0.001). The total cumulative plasma levels of the cardiac injury biomarker cardiac troponin I (cTnI) were trending downward but were not significant (999.3 ± 38.7 ng/mL vs. 1456.5 ± 64.8 ng/mL, P = 0.1867). However, plasma levels of heart-specific fatty acid binding protein (hFABP), another injury biomarker, were reduced at 2 h of reperfusion (70.3 ± 38.0 ng/mL vs. 137.3 ± 58.2 ng/mL, P = 0.0115). CONCLUSION: The IC FNL-MLT reduced IS compared to vehicle in this swine model. The FNL-MLT maybe a promising adjuvant to PCI in the treatment of acute MI.

Project description:Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.

Dataset Information

Phosphorylcholine Antibodies Preserve Cardiac Function and Reduce Infarct Size by Attenuating the Post-Ischemic Inflammatory Response.

Publications

Phosphorylcholine Antibodies Preserve Cardiac Function and Reduce Infarct Size by Attenuating the Post-Ischemic Inflammatory Response.

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