Original article
Cellular crosstalk in cardioprotection: Where and when do reactive oxygen species play a role?

https://doi.org/10.1016/j.freeradbiomed.2021.03.044Get rights and content

Highlights

  • Cellular crosstalk is vital to maintain cardiac homeostasis and repair after injury.

  • Oxidative damage spreading associate with extension of myocardial reperfusion injury.

  • Reactive oxygen species impact on different forms of communication in the heart.

  • Intercellular communication can propagate molecules implicated in redox signaling.

Abstract

A well-balanced intercellular communication between the different cells within the heart is vital for the maintenance of cardiac homeostasis and function. Despite remarkable advances on disease management and treatment, acute myocardial infarction remains the major cause of morbidity and mortality worldwide. Gold standard reperfusion strategies, namely primary percutaneous coronary intervention, are crucial to preserve heart function. However, reestablishment of blood flow and oxygen levels to the infarcted area are also associated with an accumulation of reactive oxygen species (ROS), leading to oxidative damage and cardiomyocyte death, a phenomenon termed myocardial reperfusion injury. In addition, ROS signaling has been demonstrated to regulate multiple biological pathways, including cell differentiation and intercellular communication. Given the importance of cell-cell crosstalk in the coordinated response after cell injury, in this review, we will discuss the impact of ROS in the different forms of inter- and intracellular communication, as well as the role of gap junctions, tunneling nanotubes and extracellular vesicles in the propagation of oxidative damage in cardiac diseases, particularly in the context of ischemia/reperfusion injury.

Section snippets

Cellular communication networks in cardiac health and disease

The cardiac muscle is a highly specialized tissue formed by multiple cell types. Despite being the functional unit of the heart and constituting the majority of cardiac cell mass, cardiomyocytes only account to ~33% of all populations present in the murine heart in terms of number, with endothelial cells representing around 55%, fibroblasts ~13%, leukocytes ~9% and vascular smooth muscle cells (SMCs)/pericytes ~6% [1]. Therefore, well-orchestrated communication networks are pivotal to maintain

Reactive oxygen species signaling in myocardial ischemia/reperfusion injury

Although intracellular acidosis associated with ischemia prevents MPTP opening, it is triggered during the first minutes of reperfusion due to the quick pH recovery, together with the enhanced cytosolic Ca2+ and phosphate concentrations, and exacerbated ROS production [79,80]. MPTP opening, characterized by a sudden increase in the permeability of the inner mitochondrial membrane, allows permeation of solutes with a molecular weight up to 1.5 kDa, resulting in mitochondrial depolarization, loss

How does reactive oxygen species impact on intercellular communication?

Cell-cell crosstalk can be modulated by the action of ROS, including during I/R, participating in the spread of damaging signals, as well as in cardioprotection. In the following sections, we will discuss the impact of ROS upon inter- and intracellular communication in the cardiovascular system (Fig. 2).

Can intercellular communication propagate molecules implicated in redox signaling?

An increasing body of evidence demonstrates that the different forms of intercellular communication are able to transfer ROS and antioxidant enzymes between adjacent cells or at longer distances, contributing both for the dissemination of protective and detrimental ROS-mediated signaling in multiple pathophysiological contexts [186,187]. For example, macrophage-derived EV containing functional NOX can be taken up by neurons to mediate nerve regeneration [188]. Following a localized oxidative

Redox signaling and cardioprotection

Although potentially toxic at higher doses, gaseous signaling molecules, including NO, CO and hydrogen sulfide (H2S) have been largely associated with cardioprotection, via inhibition of apoptosis and inflammation, as well as by participating in multiple cellular antioxidant defense mechanisms, making them potential therapeutic tools in several cardiac disorders. In some cases, cytoprotection mediated by NO, CO and H2S has been attributed to effects upon intercellular communication mechanisms,

Concluding remarks and future perspectives

It is generally accepted that ROS at low levels are crucial mediators of multiple intracellular signaling pathways, whereas exacerbated ROS production and/or impaired ROS scavenging due to diminished antioxidant capacity, have been associated with oxidative stress damage, namely as part of the pathophysiology of heart diseases, including I/R injury and hypertension. In addition, highly regulated mechanisms of inter and intracellular communication play crucial roles in the maintenance of

Acknowledgements/funding sources

This work was supported by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE) (under the projects HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323; CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122, UIDB/04539/2020 and UIDP/04539/2020), and by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (grants PI17/01397 and CIBERCV), the Spanish Society of Cardiology

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