Nitric Oxide and Mechano-Electrical Transduction in Cardiomyocytes

Abstract

The ability§ of the heart to adapt to changes in the mechanical environment is critical for normal cardiac physiology. The role of nitric oxide is increasingly recognized as a mediator of mechanical signaling. Produced in the heart by nitric oxide synthases, nitric oxide affects almost all mechano-transduction pathways within the cardiomyocyte, with roles mediating mechano-sensing, mechano-electric feedback (via modulation of ion channel activity), and calcium handling. As more precise experimental techniques for applying mechanical stresses to cells are developed, the role of these forces in cardiomyocyte function can be further understood. Furthermore, specific inhibitors of different nitric oxide synthase isoforms are now available to elucidate the role of these enzymes in mediating mechano-electrical signaling. Understanding of the links between nitric oxide production and mechano-electrical signaling is incomplete, particularly whether mechanically sensitive ion channels are regulated by nitric oxide, and how this affects the cardiac action potential. This is of particular relevance to conditions such as atrial fibrillation and heart failure, in which nitric oxide production is reduced. Dysfunction of the nitric oxide/mechano-electrical signaling pathways are likely to be a feature of cardiac pathology (e.g., atrial fibrillation, cardiomyopathy, and heart failure) and a better understanding of the importance of nitric oxide signaling and its links to mechanical regulation of heart function may advance our understanding of these conditions.

The role of activation of two different sGC binding sites by NO‐dependent and NO‐independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes

“…Stretch‐activated ion channels are perfectly adapted to integrate changes in the mechanical environment into an altered electrical response. Interestingly, the functional properties of some ion channels can be modified by NO (Boycott et al, 2020 ; Kazanski et al, 2011 ; Liao et al, 2006 ). Furthermore, NOS and NO production is involved in the regulation of every stage of mechanoelectrical feedback: from the initial induction of mechanical signals via integrin/cytoskeleton complexes, through the control of the action potential by modulating the activity of SACs and other ion channels, to the mediation of Ca 2+ processing underlying cardiac contraction.…”

“…NO production increases in response to various mechanical forces, a phenomenon that is of particular importance for cardiovascular function. For example, studies using NO‐sensitive dyes have shown that stretching of ventricular cardiomyocytes induces NO release (Boycott et al, 2020 ; Shim et al, 2017 ; Suárez et al, 1999 ). In some works, 20% sustained stretch was shown to induce an increase in the [NO] in within 5 min.…”

“…Nitric oxide (NO)‐sensitive soluble‐guanylyl cyclase (sGC), catalyzes the formation of intracellular messenger cyclic guanosine monophosphate (cGMP) and is considered the main receptor for intracellular NO, produced by NO synthase (NOS) in cells (Boycott et al, 2020 ; Seddon et al, 2007 ). Primary activation of sGC starts with NO binding to the sixth hemo iron coordination site in heme nitric oxide/oxygen binding domain (HNOX) in β subunit, and subsequent breaking of the bond to His105.…”

Active force generation contributes to the complexity of spontaneous activity and to the response to stretch of murine cardiomyocyte cultures

“…talin, vinculin) that are able to sense and integrate mechanical signals. It was suggested that NO stimulation of integrins then promotes NO‐mediated Ca 2+ release from the sarcoplasmic reticulum and modulates the function of L‐type Ca 2+ channels (Boycott et al., 2020). In the context of pacemaker function, this would exert a repercussion on the Ca 2+ clock and affect beat rate.…”

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

“…It would seem likely that this effect probably involves β3AR, given that this receptor also seems to be heavily localized to t-tubules [ 102 ] [ 103 ]. Nitric Oxide appears to be intimately connected to mechano-electric coupling within cardiomyocytes [ 104 ]. Unlike eNOS, nNOS can be directly activated by stretch or catecholamines in cardiac myocytes, and local NO-CaMKII by βAR [ 105 ].…”