PACAP deficiency aggravates atherosclerosis in ApoE deficient mice

Area of Science:

• Cardiovascular Research
• Immunology
• Endocrinology

Background:

• Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in cytoprotection, inflammation, and cardiovascular regulation.
• Atherosclerosis is a complex inflammatory disease of the arteries.
• The role of PACAP in atherogenesis requires further investigation.

Purpose of the Study:

• To investigate the role of PACAP in the development of atherosclerosis.
• To determine the effect of PACAP on macrophage lipid content and inflammatory cytokine release.
• To establish a novel mouse model for studying accelerated atherosclerosis.

Main Methods:

• In vitro studies using human THP-1 macrophages stimulated with oxidized low-density lipoproteins (oxLDL) and treated with PACAP38.
• In vivo studies using a novel PACAP-deficient/ApoE-deficient (PACAP^-/-/ApoE^-/-) mouse model fed standard chow or cholesterol-enriched diet.
• Analysis of atherosclerotic plaques for lumen stenosis, cellularity, and protein expression of inflammatory markers, and proteins related to autophagy, apoptosis, and necroptosis.

Main Results:

• In vitro, PACAP38 inhibited oxLDL-induced lipid storage and TNF release in macrophages.
• In vivo, PACAP^-/-/ApoE^-/- mice exhibited increased lumen stenosis under standard chow compared to ApoE^-/- mice.
• PACAP deficiency led to increased pro-inflammatory markers and markers of cell death pathways in atherosclerotic plaques, with decreased overall cell density under standard chow.

Conclusions:

• PACAP acts as an endogenous atheroprotective neuropeptide.
• PACAP deficiency accelerates atherosclerosis development, independent of cholesterol-enriched diets in this model.
• PACAP agonists show potential as anti-atherosclerotic therapeutics, although specific receptor targets require identification.