From Mitochondria to Atherosclerosis: The Inflammation Path

Abstract

Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments.

Keywords: NLRP3; atherosclerosis; inflammasome; inflammation; mitochondria; reactive oxygen species.

Figure 1

Schematic overview of atherosclerosis progression. (a) Oxidized low-density lipoprotein (oxLDL) contributes to the initial lesion in the arterial wall. (b) Endothelium cells produce pro-inflammatory cytokines, and circulating monocytes are recruited. (c) Monocytes migrate into the intima and differentiate into tissue macrophages. (d) Once in the artery wall, macrophages engulf the excessive lipids and become lipid-laden foam cells, which can accumulate and form a fatty streak. During the complex lesion progression, foam cell lysis by apoptosis and necrosis leads to the formation of a necrotic core and, together with defective efferocytosis, leads to the amplification of the inflammatory response. (e) Vascular smooth muscle cells (VSMCs) migrate from the media to the intima, where they differentiate into proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. (f) During later stages, the plaque can become unstable due to the inhibition of extracellular matrix (ECM) formation, particularly collagen production by VSMCs. In addition, ECM is degraded by proteases released by macrophages, resulting in an unstable lesion that can rupture and lead to thrombosis.

Figure 2

Relationship between mitochondria and atherosclerosis in the endothelium. Mitochondria play a key role in endothelium function, participating in several processes, such as nitric acid production, intracellular signaling, and cell death. Excessive reactive oxygen species (ROS) production leads to endothelium senescence, apoptosis, and atherosclerosis progression. Mitochondria can be damaged by oxLDL, ROS (mostly from mitochondrial origin), and the aging process. Damaged mitochondria release several mitochondrial components such as mtROS, cardiolipin and mtDNA which induce nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, leading to inflammation by increasing interleukin 1β and 18 maturation. Chronic NLRP3 activation will eventually lead to more mitochondrial damage by promoting mitochondrial calcium influx. Also, higher ROS levels disrupt the NO balance by boosting mitochondrial arginase II activity and causing eNOS degradation. In endothelium, the reduction of NO levels may also promote endothelial dysfunction and atherosclerosis. Most of these ROS-derived alterations are prevented by antioxidants enzymes (green block arrows).