Sarcolemmal dependence of cardiac protection and stress‐resistance: roles in aged or diseased hearts

Abstract

Disruption of the sarcolemmal membrane is a defining feature of oncotic death in cardiac ischaemia-reperfusion (I-R), and its molecular makeup not only fundamentally governs this process but also affects multiple determinants of both myocardial I-R injury and responsiveness to cardioprotective stimuli. Beyond the influences of membrane lipids on the cytoprotective (and death) receptors intimately embedded within this bilayer, myocardial ionic homeostasis, substrate metabolism, intercellular communication and electrical conduction are all sensitive to sarcolemmal makeup, and critical to outcomes from I-R. As will be outlined in this review, these crucial sarcolemmal dependencies may underlie not only the negative effects of age and common co-morbidities on myocardial ischaemic tolerance but also the on-going challenge of implementing efficacious cardioprotection in patients suffering accidental or surgically induced I-R. We review evidence for the involvement of sarcolemmal makeup changes in the impairment of stress-resistance and cardioprotection observed with ageing and highly prevalent co-morbid conditions including diabetes and hypercholesterolaemia. A greater understanding of membrane changes with age/disease, and the inter-dependences of ischaemic tolerance and cardioprotection on sarcolemmal makeup, can facilitate the development of strategies to preserve membrane integrity and cell viability, and advance the challenging goal of implementing efficacious 'cardioprotection' in clinically relevant patient cohorts. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

“…Dietary modulation of caveolar domains and proteins [ 29 , 30 , 31 , 32 , 33 ], mitochondrial function [ 22 ] or inflammation [ 34 ] might be of particular benefit in diabetes. Hearts of diabetic patients appear sensitized to damage [ 35 ] and desensitized to cardioprotection [ 36 ], and disruption of caveolae and caveolar proteins [ 29 , 30 , 31 , 32 , 37 ] governing ischemia-reperfusion (I-R) tolerance and cardioprotection [ 38 , 39 , 40 , 41 , 42 ] is implicated [ 42 ]. Similar mechanisms may underlie influences of aging on stress-resistance and survival signaling [ 43 ].…”

Cardiac Muscle Membrane Stabilization in Myocardial Reperfusion Injury

“…Whereas the pathways leading to cardiac I/R injury are multifold and complex 18, 41, 42, we and others have established a sound premise that a clear approach for a clinically meaningful treatment would be one that would directly enhance cardiac membrane stability in I/R (43). Given that cardiac sarcolemma damage is a well-established hallmark of I/R injury, it is surprising this has received relatively little direct investigation as a possible target for I/R treatment development (44).…”

Hurdles to Cardioprotection in the Critically Ill

“…Using tissue microarray, Kong and colleagues demonstrated that collagen III is reduced in the aortic wall extracellular matrix of AMI patients, and suggested this reduction may enhance plaque vulnerability, and thus the propensity for vessel occlusion and AMI [25]. Modification of membrane lipids is an important factor in the development of cellular injury, tolerance to ischemia and dependence of cardioprotective/cytoprotective signaling [26,27]. Indeed, unique lipid profiling of ceramides in plasma (but not aortic tissue) following AMI, have recently been demonstrated to predict long-term incidence of detrimental cardiac and cerebrovascular events [28].…”