Abstract
Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, NfκB, TNFα, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear.
Highlights
Coronary artery disease (CAD) is the leading cause of mortality worldwide [1] and ensues from the narrowing of the blood vessel lumen due to the accumulation of atherosclerotic plaques
Where required raw data was tested for normality using the Shapiro–Wilk test and Kolmogorov–Smirnov tests embedded in GraphPad with the alpha-value set to 0.05; these analyses indicated that data from acute myocardial infarction (AMI) groups were normally distributed
Given that 3-chlorotyrosine is an established marker of hypochlorous acid (HOCl) mediated damage, these results indicate that: (i) reperfusion post experimental AMI induces the activation of neutrophil-MPO to yield HOCl-mediated damage to cardiac tissue, and (ii) the supplemented nitroxide successfully reaches the myocardium and exerts its inhibitory activity on MPO, thereby decreasing MPO-activity and validating the study design
Summary
Coronary artery disease (CAD) is the leading cause of mortality worldwide [1] and ensues from the narrowing of the blood vessel lumen due to the accumulation of atherosclerotic plaques. The introduction of reperfusion therapy has presented a clinical paradox; on the one hand, it greatly contributes to the increase in survival rates post-acute myocardial infarction (AMI), due to relief of the blockage in the affected coronary artery and resumption of blood flow to the infarcted myocardium [3]. It results in reperfusion injury, consisting of a series of insults to the myocardium due to the production of reactive oxygen species (ROS), mitochondrial dysfunction, and immune cell infiltration and activation [4]. Neutrophils release various proteolytic enzymes that are essential for the formation of non-contractile collagen scars, an essential component of myocardial healing post-AMI. Neutrophils degranulate and release the enzyme myeloperoxidase (MPO), an enzyme that catalyses the formation of hypohalous acids, including hypochlorous acid (HOCl), the predominant product formed under physiological conditions. HOCl induces the chlorination of tyrosine residues, producing the biomarker 3-chlorotyrosine, which is used for quantification of HOCl-induced protein damage [8,9]
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