Neutrophil-Mediated Cardiac Damage After Acute Myocardial Infarction: Significance of Defining a New Target Cell Type for Developing Cardioprotective Drugs

Abstract

Significance: Acute myocardial infarction (AMI) is a leading cause of death worldwide. Post-AMI survival rates have increased with the introduction of angioplasty as a primary coronary intervention. However, reperfusion after angioplasty represents a clinical paradox, restoring blood flow to the ischemic myocardium while simultaneously inducing ion and metabolic imbalances that stimulate immune cell recruitment and activation, mitochondrial dysfunction and damaging oxidant production. Recent Advances: Preclinical data indicate that these metabolic imbalances contribute to subsequent heart failure through sustaining local recruitment of inflammatory leukocytes and oxidative stress, cardiomyocyte death, and coronary microvascular disturbances, which enhance adverse cardiac remodeling. Both left ventricular dysfunction and heart failure are strongly linked to inflammation and immune cell recruitment to the damaged myocardium. Critical Issues: Overall, therapeutic anti-inflammatory and antioxidant agents identified in preclinical trials have failed in clinical trials. Future Directions: The versatile neutrophil-derived heme enzyme, myeloperoxidase (MPO), is gaining attention as an important oxidative mediator of reperfusion injury, vascular dysfunction, adverse ventricular remodeling, and atrial fibrillation. Accordingly, there is interest in therapeutically targeting neutrophils and MPO activity in the setting of heart failure. Herein, we discuss the role of post-AMI inflammation linked to myocardial damage and heart failure, describe previous trials targeting inflammation and oxidative stress post-AMI, highlight the potential adverse impact of neutrophil and MPO, and detail therapeutic options available to target MPO clinically in AMI patients. Antioxid. Redox Signal. 33, 689-712.

Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases

“…The activated cytokines will induce inflammation in these cells. Among them, neutrophils are the predominant early responder [ 95 ]. Neutrophils recruited to the infarct zone contain high levels of NOX2 and MPO, which facility the production of ROS.…”

Oral pre-treatment with thiocyanate (SCN−) protects against myocardial ischaemia–reperfusion injury in rats

“…3 ). However, the level of 2D10G9 staining decreased from the site of ligation to the apex, consistent with the greatest extent of neutrophil accumulation at sites proximal to the infarction zone 20 . Examination of the extent of apoptosis and necrosis in the tissues at various time points after IR injury in both the non-supplemented and SCN – dosed animals may shed further light on the mechanisms of damage propagation and its prevention.…”

“…Overall, supplementation with SCN − decreased the extent of 2D10G9 epitope recognition in the hearts following IR injury, consistent with a decreased extent of protein modification by MPO-derived HOCl. Interestingly, this was not the case at the site of ligation, where a similar extent of fluorescence from 2D10G9 epitopes was seen in the absence and presence of SCN − , despite the prediction of a high concentration of neutrophils in this region 20 , though this was not assessed which is a shortcoming of this study. This lack of difference may be due to the extensive tissue necrosis at this site (cf.…”

“…The over-production of oxidants by activated neutrophils, particularly hypochlorous acid (HOCl), which is generated by MPO from H 2 O 2 and Cl − , contributes to the damage sustained by the myocardium following reperfusion (reviewed 7 , 8 , 20 ). While Cl − is the most abundant substrate for MPO, other halide (bromide, Br − ; iodide, I − ) and pseudohalide (thiocyanate, SCN − ) ions can also be oxidized yielding hypobromous acid, hypoiodous acid and hypothiocyanous acid (HOSCN), respectively (reviewed 21 ).…”

Myeloperoxidase-Derived 2-Chlorohexadecanal Is Generated in Mouse Heart during Endotoxemia and Induces Modification of Distinct Cardiomyocyte Protein Subsets In Vitro

“…Neutrophil accumulation and activation is accompanied by the release of cytotoxic enzymes including neutrophil-derived elastase (NE) and MPO, resulting in local (oxidative) stress conditions. In fact, MPO is involved in cardiac remodeling and dysfunction through multiple pathways [44]. MPO-derived oxidants increase myocardial collagen deposition [45], play a major role in left ventricular remodeling after myocardial infarction (MI) [46], and increase vulnerability to atrial fibrillation [47].…”