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Review
. 2019 Jun 1;115(7):1156-1166.
doi: 10.1093/cvr/cvy314.

Circulating blood cells and extracellular vesicles in acute cardioprotection

Sean M Davidson  1 , Ioanna Andreadou  2 , Lucio Barile  3 , Yochai Birnbaum  4 , Hector A Cabrera-Fuentes  5   6   7   8   9 , Michael V Cohen  10   11 , James M Downey  11 , Henrique Girao  12   13 , Pasquale Pagliaro  14   15 , Claudia Penna  14   15 , John Pernow  16 , Klaus T Preissner  17 , Péter Ferdinandy  18   19
Affiliations
Review

Circulating blood cells and extracellular vesicles in acute cardioprotection

Sean M Davidson et al. Cardiovasc Res. .

Abstract

During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

Keywords: Cardioprotection; Exosomes; Haematopoietic cells; Ischaemia; Reperfusion.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Ischaemia and reperfusion causes the activation of platelets, which subsequently release a multitude of factors with divergent effects on infarct size. These include exosomes and microvesicles (both types of extracellular vesicles), SDF-1α, chemerin, sphingosine-1 phosphate, and PAF. P2Y12 inhibitors can prevent platelet activation and can also reduce infarct size (see text for details).
Figure 2
Figure 2
Erythrocytes contain endothelial nitric oxide synthase (NOS3), which protects the heart via the production of nitric oxide (NO), S-nitrosothiols (S-NO), or nitrite. Since NOS3 competes with arginase for the common substrate arginine, inhibition of arginase can be cardioprotective.
Figure 3
Figure 3
Initiation, amplification and feedback anticoagulant mechanisms in the coagulation cascade. The different phases, from initiation of coagulation due to exposure of tissue factor and binding of its ligand factor VII/VIIa either at a wound/extravascular site or in the intravascular compartment (microvesicles), designated as ‘extrinsic pathway’, to amplification and production of thrombin by the positive feedback reactions of the ‘intrinsic pathway’ are indicated. In parallel to fibrin clot formation, the majority of thrombin will distantly bind to its endothelial cell receptor thrombomodulin to induce the activation of protein C (PC) into APC, which limits further thrombin production by degrading the procoagulant cofactors VIIIa and Va. While these reactions are sufficient to achieve wound healing upon physiological haemostasis, when an atherosclerotic plaque ruptures, thrombogenic substrates are exposed that can initiate (auto-) activation of the factor XII-dependent reactions of the contact phase, resulting in enhanced thrombin generation and hence, fibrin clot formation and eventually thrombosis. The inhibitors mentioned in the text are indicated in red.
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