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Mitochondrial DAMPs and altered mitochondrial dynamics in OxLDL burden in atherosclerosis

Bisma Khwaja1, Finosh G Thankam1, Devendra K Agrawal2

  • 1Department of Translational Research, Western University of Health Sciences, Pomona, CA, 91766, USA.

Molecular and Cellular Biochemistry
|January 25, 2021
PubMed

Insights

Mitochondrial damage-associated molecular patterns (mtDAMPs) and oxidized LDL (oxLDL) trigger sterile inflammation in atherosclerosis by activating the NLRP3 inflammasome. This pathway promotes inflammatory cytokines, driving plaque formation and cardiovascular disease.

Area of Science:

  • Cardiovascular Pathology
  • Immunology
  • Molecular Biology

Background:

  • Atherosclerosis leads to severe cardiovascular diseases, with oxidized low-density lipoprotein (oxLDL) accumulation being a key factor.
  • Emerging research highlights mitochondrial damage-associated molecular patterns (mtDAMPs) as critical initiators of sterile inflammation in atherosclerosis, acting alongside oxLDL.

Purpose of the Study:

  • To critically review and discuss the central role of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome in mtDAMP-induced sterile inflammation in atherosclerosis.
  • To explore the involvement of specific components like caspase-1, pregnane X receptor (PXR), adenosine monophosphate activated protein kinase (AMPK), protein phosphatase 2A (PP2A), and thioredoxin-interacting protein (TXNIP).
  • To examine the role of downstream cytokines, including interleukin-1β (IL-1β) and IL-18, as potential mediators of atherosclerosis.

Main Methods:

  • Literature review and critical discussion of existing research on mtDAMPs, oxLDL, and the NLRP3 inflammasome in atherosclerosis.
  • Analysis of signaling pathways involved in mtDAMP-mediated inflammation.
  • Identification of key molecular components and downstream cytokines implicated in the atherosclerotic process.

Main Results:

  • mtDAMPs, including mitochondrial DNA (mtDNA) and other components, are implicated in proatherogenic roles.
  • mtDAMPs activate the NLRP3 inflammasome, leading to the secretion of pro-inflammatory cytokines like IL-1β.
  • This inflammatory cascade contributes to vascular smooth muscle and fibroblast proliferation, arterial wall thickening, and plaque formation.

Conclusions:

  • The NLRP3 inflammasome plays a central role in mtDAMP-induced sterile inflammation in atherosclerosis.
  • Understanding the interplay between mtDAMPs and oxLDL offers significant potential for developing novel therapeutic strategies against atherosclerosis.
  • Targeting the NLRP3 inflammasome pathway presents a promising avenue for novel therapeutic interventions in atherosclerosis.

Keywords:
AtherosclerosisDamage-associated molecular patternsInflammasomesMitochondrial DAMPNLRP3OxLDL

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