**4.1. Blood vessel**

ing proteins, DNA, phospholipids and other biological structures. During reperfusion, PAF, TNF-α, IL-6, IL-1β, granulocyte-macrophage colony-stimulating factor, complement fraction C5a and the ROS themselves stimulate endothelial and neutrophil ROS production. [49], [61],[62] On the other hand, ROS activate nuclear factor-κB, promote cytokine production (e.g., TNF-α, IL-6, PAF), and induce the synthesis and expression of endothelial and leuko‐

In the reperfused tissue, the principal sources of ROS are neutrophil NADPH-oxidase, xan‐ thine oxidase, mitochondria and the arachidonic acid pathways. [64]-[66] The massive ROS production quickly exceeds the capacity of cellular defense systems (catalase, superoxide dismutase, glutathione peroxidase and vitamins C and E). ROS directly cause much struc‐ tural damage, increase the susceptibility to the opening of the mitochondrial permeability

ROS can also be produced by monoamine oxidase (MAO) of the outer mitochondrial mem‐ brane. MAO transfers electrons from amine compounds with oxygen to produce hydrogen peroxide. [68] p66Shc, a cytosolic adaptor protein for tyrosine kinase receptors that has been implicated in signal transduction, translocates to the mitochondrial matrix during reperfu‐ sion and oxidizes the reduced cytochrome *c*, which generates oxygen peroxide. [67],[69]

Reperfusion is vital for the functional recovery of an ischemic organ but also initiates the apoptosis pathways. [70],[71] Apoptosis is an active mechanism of cellular death, is geneti‐ cally programmed, consumes energy, requires the expression or activation of specific en‐ zymes, and can be induced by the oxidative stress of reperfusion. Reperfusion-induced apoptosis occurs in many organs, including heart, brain, kidney and liver. The reperfusion of an organ can induce apoptosis in other, distant organs. For example, reperfusion of a low‐ er limb or the small bowel can induce apoptosis of cardiomyocytes or lung cells, respective‐ ly. [72],[73] The TNF-α production by the reperfused organ seems to play a crucial part in the induction of apoptosis. [70],[74]-[76] TNF-α initiates a receptor-dependent death path‐ way by activating downstream caspases. [70],[76],[77] Other causes of reperfusion-induced apoptosis are also important: mitochondrial depolarization, high intracellular calcium, mPTP opening and the release of some mitochondrial proteins into the cytoplasm, such as cytochrome *c*. When this protein is released from mitochondria into the cytoplasm, it inter‐ acts with apoptotic protease activating factor-1 (Apaf-1) and ATP to form the apoptosome, a large oligomeric protein complex that can activate caspase 9, which activates the caspase-de‐

Endothelial cell apoptosis precedes and influences the apoptosis of the subjacent parenchymal cells. For example, a reduction in endothelial apoptosis decreases the apoptosis of subjacent cardiomyocytes. This suggests that signals emanating from the endothelium during apoptosis

transition pore, activate immune and endothelial cells and induce apoptosis. [67]

cyte adhesion molecules. [15],[41],[63]

24 Artery Bypass

**3.4. Ischemia-reperfusion-induced apoptosis**

pendent apoptosis pathway.

can induce or reinforce that of the cardiomyocytes.

According to the level of the vascular system considered (small arteries, capillaries and post‐ capillary veins), the repercussions of I/R are identical, but the clinical pictures differ.
