Cardiac Muscle Membrane Stabilization in Myocardial Reperfusion Injury

Abstract

Highlights In myocardial ischemia, the integrity of the cardiac sarcolemma is severely stressed in the critical earliest moments upon reperfusion. Bolstering sarcolemma integrity improves myocyte survival. This review focuses on cardiac sarcolemma stability and its role as a therapeutic target in ischemia-reperfusion injury. Synthetic block copolymers have been shown to interface with the muscle membrane to confer membrane stabilization during stress. Integrated multidisciplinary research teams, spanning cardiology, physiology, chemistry, and chemical engineering are essential to guide future mechanistic and translational studies of novel chemical-based membrane stabilizers for preserving viable heart muscle during ischemia-reperfusion injury in human patients.

Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

“…Finally, P188-treated mdx mice undergoing chronic isoproterenol stress had some improvements in in vivo cardiac function after two and four weeks [158], and a large animal model of DMD showed significant improvement in in vivo cardiac function after chronic P188 therapy [68]. The reader is referred to excellent recent reviews for more details on this topic [63,166].…”

Ischemia reperfusion injury provokes adverse left ventricular remodeling in dysferlin-deficient hearts through a pathway that involves TIRAP dependent signaling

“…The findings that the increase in myocardial inflammation and adverse LV remodeling observed in Dysf −/− mouse hearts was abrogated in Dysf −/− / Tirap −/− mouse hearts, but not in chimeric Tirap −/− → Dysf −/− mouse hearts suggested that the adverse phenotype in the Dysf −/− mouse hearts was cardiac autonomous. Noting that prior studies demonstrated that dysferlin plays an important role in membrane sealing 17 , 18 , and that the membrane resealing reagent Poloxamer 188 (P188) was cardioprotective in Dysf −/− mouse hearts subjected to I/R injury ex vivo 2 , 10 , we sought to determine whether treatment with P188 would rescue the phenotype of the Dysf −/− mice subjected to I/R injury in vivo. We first confirmed that in our hands P188 (10 µM) improved LV functional recovery (p = 0.007) in Dysf −/− mouse hearts subjected to 30 min of no-flow ischemia, followed by 60 min of reperfusion ex vivo (Supplemental Figure S3 ), as suggested by Martindale et al 10 .…”

“…Uaesoontrachoon and colleagues hypothesized that breaches in the skeletal muscle membrane in dysferlin-deficient mice resulted in the release of endogenous danger signals that bind to cognate TLR ligands on muscle and immune cells, which in turn activate downstream processes that lead to the recruitment of inflammatory cells that worsen the initial damage caused by the dysferlin gene defect 11 . Several studies have used chemical-based membrane stabilizers, such as P188, to protect striated muscle membranes 2,10,[26][27][28] . P188 is composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, and is currently approved by the Food and Drug Administration as an antiviscosity agent.…”

“…Given the importance of the sarcolemma to cell viability, it is not surprising that cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes. These include sarcolemma phospholipid rearrangements at the site of very small disruptions/injury in order to promote membrane resealing, as well as several endogenous mechanisms that are activated in order to repair damage to preserve muscle cell integrity and viability (reviewed in 1 , 2 ).…”

<p>Postconditioning Protection Against Myocardiocyte Anoxia/Reoxygenation Injury From Penehyclidine Hydrochloride</p>

“…This is referred to as ischemia-reperfusion injury (IRI). [1][2][3] For the past decade, researchers have explored ways of reducing IRI, including preconditioning and postconditioning. In order to understand the chain of events that ultimately result in IRI, as well as the mechanism from which IRI could be protected by postconditioning treatment, we designed an in vitro experiment using H9c2 cell models through A/R procedures.…”