Mitochondrial DAMPs and altered mitochondrial dynamics in OxLDL burden in atherosclerosis

Abstract

Atherosclerosis results in life-threatening cardiovascular pathologies, including ischemic heart disease, stroke, myocardial infarction, and peripheral arterial disease. The role of increased serum low-density lipoprotein (LDL) and resultant accumulation of oxidized-LDL (oxLDL) in atheroma formation is well established. Recent findings elucidate the significance of mitochondrial damage-associated molecular patterns (mtDAMPs) in triggering sterile inflammation in concert with oxLDL. The mtDAMPs including mitochondrial DNA (mtDNA), cytochrome C, cardiolipin, heat shock protein 60 (HSP60), mitochondrial transcription factor A (TFAM), and N-formyl peptides, are expected to possess proatherogenic roles. However, limited data are available in the literature. The mtDAMPs initiate sterile inflammation in atherosclerotic lesions via numerous signaling pathways, most of which converge to the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Priming the activation of the NLRP3 inflammasome, mtDAMPs promote secretion of proinflammatory cytokines, including interleukin-1β (IL-1β), implicated in atherosclerotic lesions through vascular smooth muscle and fibroblast proliferation, arterial wall thickening, and plaque formation. In this article we critically reviewed and discussed the central role of the NLRP3 inflammasome in mtDAMP-induced sterile inflammation in atherosclerosis with specific components including caspase-1, pregnane X receptor (PXR), adenosine monophosphate activated protein kinase (AMPK), protein phosphatase 2A (PP2A), thioredoxin-interacting protein (TXNIP), and downstream cytokines including IL-1β and IL-18 as potential mediators of atherosclerosis. Better understanding of the proinflammatory effects of mtDAMPs and its pathological association with oxLDL possess immense translational significance for novel therapeutic intervention.