Abstract
The cardiomyocyte plasma membrane, termed the sarcolemma, is fundamental for regulating a myriad of cellular processes. For example, the structural integrity of the cardiomyocyte sarcolemma is essential for mediating cardiac contraction by forming microdomains such as the t-tubular network, caveolae and the intercalated disc. Significantly, remodelling of these sarcolemma microdomains is a key feature in the development and progression of heart failure (HF). However, despite extensive characterisation of the associated molecular and ultrastructural events there is a lack of clarity surrounding the mechanisms driving adverse morphological rearrangements. The sarcolemma also provides protection, and is the cell’s first line of defence, against external stresses such as oxygen and nutrient deprivation, inflammation and oxidative stress with a loss of sarcolemma viability shown to be a key step in cell death via necrosis. Significantly, cumulative cell death is also a feature of HF, and is linked to disease progression and loss of cardiac function. Herein, we will review the link between structural and molecular remodelling of the sarcolemma associated with the progression of HF, specifically considering the evidence for: (i) Whether intrinsic, evolutionary conserved, plasma membrane injury-repair mechanisms are in operation in the heart, and (ii) if deficits in key ‘wound-healing’ proteins (annexins, dysferlin, EHD2 and MG53) may play a yet to be fully appreciated role in triggering sarcolemma microdomain remodelling and/or necrosis. Cardiomyocytes are terminally differentiated with very limited regenerative capability and therefore preserving cell viability and cardiac function is crucially important. This review presents a novel perspective on sarcolemma remodelling by considering whether targeting proteins that regulate sarcolemma injury-repair may hold promise for developing new strategies to attenuate HF progression.
Highlights
Heart failure (HF) is a terminal illness for which there is no cure, with a heart transplant being the only option for survival
While HF is a multi-faceted clinical syndrome, a common aetiology is the progressive development of morphological remodelling of the myocardium, which leads to a decline in contractile function and insufficient blood being pumped to meet the demands of the body
Replacement fibrosis is associated with cardiomyocyte death with extracellular matrix (ECM) accumulating in response to loss of cardiomyocytes which in turn contributes towards compromised cardiac function and contractility (Segura et al 2014)
Summary
Heart failure (HF) is a terminal illness for which there is no cure, with a heart transplant being the only option for survival. HF is characterised by adverse structural alterations in response to pressure and volume overload; these include an increase in left ventricular (LV) mass, cardiomyocyte hypertrophy and inter-myocyte fibrosis, the extent of which can be correlated to systolic dysfunction and patient survival rates (Hill and Olson 2008). Underpinning e–c coupling and Ca2+ cycling is the precise spatial organisation of a host of ion channels, transporters, receptors and regulatory proteins, maintained in a specific geometry by specialised microdomains formed by the cardiomyocyte plasma membrane, termed the sarcolemma, and the SR. From a novel perspective, we will consider if deficits in the repair machinery occurr in HF and may be a mediator of dysfunctional contractility and cell death due to loss of sarcolemma structural integrity
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