The Role of Mitochondrial Reactive Oxygen Species in Cardiovascular Injury and Protective Strategies

Abstract

Ischaemia/reperfusion (I/R) injury of the heart represents a major health burden mainly associated with acute coronary syndromes. While timely coronary reperfusion has become the established routine therapy in patients with ST-elevation myocardial infarction, the restoration of blood flow into the previously ischaemic area is always accompanied by myocardial injury. The central mechanism involved in this phenomenon is represented by the excessive generation of reactive oxygen species (ROS). Besides their harmful role when highly generated during early reperfusion, minimal ROS formation during ischaemia and/or at reperfusion is critical for the redox signaling of cardioprotection. In the past decades, mitochondria have emerged as the major source of ROS as well as a critical target for cardioprotective strategies at reperfusion. Mitochondria dysfunction associated with I/R myocardial injury is further described and ultimately analyzed with respect to its role as source of both deleterious and beneficial ROS. Furthermore, the contribution of ROS in the highly investigated field of conditioning strategies is analyzed. In the end, the vascular sources of mitochondria-derived ROS are briefly reviewed.

Figure 1

Mitochondrial ROS contribution to I/R injury. Cellular hypoxia secondary to ischaemia results in disruption of ETC activity in the IMM (inner mitochondrial membrane) with subsequent ROS production. Increased activity of MAOs, NADPH oxidase, and p66^shc; conformational changes of xanthine oxidase; and/or NO synthase uncoupling further amplify ROS production upon reoxygenation. Increased mitochondrial ROS damages mtDNA and RNA with ETC impairment. Dysfunctional ETC will amplify ROS generation, leading to a vicious cycle of mitochondrial cumulative damage, decreased mitochondrial membrane potential (Δψ _m) and respiration, mPTP opening with cellular swelling and Ca²⁺ dysregulation, and oxidation of lipids and proteins. Postischaemic ROS generation also stimulates an inflammatory response, with the release of chemical mediators and expression of adhesion molecules by endothelial cells and leukocytes. ROS-dependent activation of MMPs (matrix metalloproteinases) is also responsible for the functional impairment of several proteins and receptors. The inflammatory response and the activation of leucocytes and platelets trigger the narrowing of capillaries during reperfusion, accelerating the progression towards cardiomyocyte death. (Illustration realized thanks to Servier Medical Art.)