Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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release and cell death via caspase-dependent and independent mechanisms [ 36 ]

(Fig. 10.1 and Video 1).

Intracellular Ca2+ overload is exacerbated during reperfusion, because SERCA

and PMCA are still inactive and now cytosolic sodium is extruded in exchange for

calcium by the Na+/Ca2+ exchanger (NCX). To prevent lethal increase in cytosolic

calcium, mitochondria import Ca2+ into its matrix (via a Ca2+ uniporter), paradoxi-

cally if in excess mitochondrial Ca2+ activates MPTP opening. Free intracellular

calcium also activates proteases (calpains), which damage myofibrils, degrade cyto-

skeletal, endoplasmic reticulum and mitochondrial proteins, and trigger intracellu-

lar signaling pathways (Ca2+/calmodulin-dependent protein kinases) that may

conduct to cell death. Furthermore, inflammatory response can be elicited with

reperfusion, due to ischemic cardiomyocytes release of proteins (damage- associated

molecular patterns  - DAMP) and expression of toll-like receptors (TLR) causing

leucocyte recruitment [ 37 ]. Activated neutrophils secrete ROS and leukotrienes and

reduce endothelial NO availability, leading to microvascular damage (vasomotor

dysfunction, increased permeability and angiogenesis) and possibly new vascular

occlusion (due to endothelial cell swelling and neutrophil or platelet plugging),

which hamper complete coronary flow restoration or lead to subsequent new isch-

emic episode [ 38 – 40 ].

Ischemia and reperfusion-induced cardiomyocyte homeostatic derangements

may culminate with cell death. Major patterns of cell death are necrosis (also called

oncosis), apoptosis and autophagy. Necrosis is defined as an uncontrolled process,

characterized by organelle and cell swelling (therefore the term oncosis – cell death

by oncotic pressure), plasmatic membrane rupture and intracellular content leakage,

giving rise to inflammation and scar tissue formation. Recent evidence of molecular

pathways activating necrosis outdated the uncontrolled nature of this pattern of cell

death, giving rise to the term necroptosis. Although its pathway shares upstream

signaling elements with apoptosis (such as TNF), it is a caspase independent and

morphologically distinct form of cell death [ 41 ]. Differently, apoptosis is a geneti-

cally programmed, energy-dependent (ATP consuming) process that involves

nuclear condensation, DNA fragmentation, phagocytosis of apoptotic bodies in the

absence of inflammatory reaction. Specific extracellular (involving activation of Fas

and TNFα receptors) and intracellular (mitochondria mediated) pathways regulate

the apoptotic process mediated by caspase proteases. Autophagy, the third mecha-

nism of cell death, is actually a housekeeping and cell survival mechanism, whereby

cell components (including damaged or unnecessary organelles) are captured

degraded and recycled through vesicles that fuse to lysosomes. It is a process regu-

lated by autophagy-related genes (Atg), however under pathological conditions

uncontrolled autophagy may lead to cell death [ 42 , 43 ].

All types of myocardial cell death have been identified after IRI, although rela-

tive contribution of each type, as well as the moment of its trigger (during ischemia

or reperfusion), remain obscure issues [ 44 ]. Experimental evidence points to initial

cell death during prolonged ischemia, with reperfusion greatly exacerbating the

magnitude of cardiomyocyte loss [ 45 ]. Even after periods of non-lethal ischemia,

reperfusion injury triggers cell death. Importantly, reperfusion can elicit two waves

10 Cardiac Ischemia/Reperfusion Injury: The Bene cial Effects of Exercise