Chonnam Med J.  2010 Dec;46(3):129-139. 10.4068/cmj.2010.46.3.129.

Mechanism of Ischemia and Reperfusion Injury to the Heart: From the Viewpoint of Nitric Oxide and Mitochondria

Affiliations
  • 1Cardiology Division, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea. mylovekw@hanmail.net

Abstract

After an acute myocardial infarction, early and successful myocardial reperfusion is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. However, the process of restoring blood flow to the ischemic myocardium can induce injury. This phenomenon,termed myocardial reperfusion injury, can paradoxically reduce the beneficial effects of myocardial reperfusion and lead to lethal damage to myocardium. During cardiac ischemia-reperfusion (IR) injury, excessive generation of reactive oxygen species (ROS), overload of intracellular Ca2+, H+ leakage at the mitochondrial level, inflammation, and metabolic modulations lead to opening of the mitochondrial permeability transition pore(PTP) on reperfusion. This can result in the depletion of ATP, irreversible oxidation of proteins, lipids, and DNA within the cardiomyocyte, and can trigger apoptosis. In contrast, mitochondria also plays an important role in the cardioprotective signaling processes of ischemic preconditioning (IPC), to prevent IR injury. Nitric oxide (NO) generated constitutively within the heart has long been known to influence myocardial function. But, Nitric oxide (NO) has emerged as a potent effector molecule for a variety of cardioprotective strategies, including IPC. Whereas NO is most noted for its activation of the "classic" soluble guanylate cyclase (sGC) signaling pathway, emerging evidence indicates that NO can directly act on mitochondria, independent of the sGC pathway, affording acute cardioprotection against IR injury. These effects of NO on mitochondria and mitochondrial role during IR injury are the focus of this review.

Keyword

Myocardial infarction; Ischemia-reperfusion; Nitric oxide; Mitochondria

MeSH Terms

Adenosine Triphosphate
Apoptosis
DNA
Guanylate Cyclase
Heart
Inflammation
Ischemia
Ischemic Preconditioning
Mitochondria
Myocardial Infarction
Myocardial Reperfusion
Myocardial Reperfusion Injury
Myocardium
Myocytes, Cardiac
Nitric Oxide
Permeability
Proteins
Reactive Oxygen Species
Reperfusion
Reperfusion Injury
Adenosine Triphosphate
DNA
Guanylate Cyclase
Nitric Oxide
Proteins
Reactive Oxygen Species

Figure

  • Fig. 1 The concept of lethal reperfusion injury. During ischemia, irreversible cell injury leading to cell death occurs within the ischemic risk zone in a time-dependent manner. In the absence of reperfusion, ischemic injury progressively kills more and more cells, eventually accounting for near total cell death (broken line). Reperfusion halts the process of ischemic cell death but in its early stages imposes injury that results in further cell death, beyond that due to the ischemic period: this is lethal reperfusion injury. The net result, however, is that the reperfused tissue sustains less cell death than would occur in ischemic tissue without reperfusion. Hence, targeting cell death due to reperfusion has the potential to maximize cell salvage. Adapted from Garcia-Dorado and Piper.1

  • Fig. 2 Signaling pathways in IPC. The three main signaling pathways implicated in the mechanism of IPC are the insulin → PI3k kinase → Akt axis (110), the GPCR → DAG → PKC → axis, and the NO → PKG → K+ATP channel axis. Key convergence points at the mitochondrial level are the phosphorylation and inactivation of GSK-3 β, ROS generation by the ETC, K+ATP channel opening, and the inhibition of PTP opening. Roles are also proposed for NO, mitochondrial uncoupling (H+ leak), transient opening or "flickering" of the PTP. The pathways by which various protective agents elicit cardioprotection also are shown. Arrows , positive or stimulatory effects; T-bars, inhibitory effects.


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