Abstract
Genetic, dietary and immune factors contribute to the pathogenesis of atherosclerosis in humans and mice. Complement activation is an integral part of the innate immune defence but also shapes cellular responses and influences directly triglyceride synthesis. Deficiency of Factor B of the alternative pathway (AP) of complement is beneficial in LDLR−/− mice fed a high fat diet. The serum glycoprotein properdin is a key positive regulator of the AP but has not been studied in experimental atherosclerosis. Atherosclerosis was assessed after feeding low fat (LFD) or high fat (HFD) Western type diets to newly generated LDLR−/− ProperdinKO (LDLR−/−PKO) and LDLR−/−PWT mice. Lipids, lymphocytes and monocytes were similar among genotypes, genders and diets. Complement C3, but not C3adesarg, levels were enhanced in LDLR−/−PKO mice regardless of diet type or gender. Non-esterified fatty acids (NEFA) were decreased in male LDLR−/−PKO fed a HFD compared with controls. All mice showed significant atherosclerotic burden in aortae and at aortic roots but male LDLR−/− mice fed a LFD were affected to the greatest extent by the absence of properdin. The protective effect of properdin expression was overwhelmed in both genders of LDLR−/−mice when fed a HFD. We conclude that properdin plays an unexpectedly beneficial role in the development and progression of early atherosclerotic lesions.
Highlights
Atherosclerosis is a progressive inflammatory condition resulting in cellular changes in the arterial intima with fatty deposits, socalled atheroma
Levels of non-esterified fatty acids (NEFA) liberated by hydrolysis of triglycerides by hormone sensitive lipase were significantly decreased in male LDLR2/2 PKO mice on a high fat diets (HFD), which had the highest mean body weight
C3 was increased in plasma of male and female LDLR2/2 PKO versus LDLR2/2 PWT mice fed a LFD or HFD (Table 1) consistent with impaired alternative pathway (AP) activity in LDLR2/2 PKO, which we confirmed using the standard rabbit red blood cell lysis assay
Summary
Atherosclerosis is a progressive inflammatory condition resulting in cellular changes in the arterial intima with fatty deposits, socalled atheroma. The innate immune system is central to the pathology and plays a role in initiation and progression of the disease [1]. Complement (C) and complement activation are key elements of the innate immune system. The enzymatic generation of C3a from C3 and subsequently C5a from C5 with relevant receptors (C3aR, C5aR and C5L2) leads to complement-mediated chemoattraction of inflammatory cells. The complement anaphylatoxins C3a and C5a bind to receptors expressed by plaque intima macrophages, T cells, mast cells, endothelial and medial smooth muscle cells and have a role in orchestrating the inflammatory component of atherosclerosis. Our recent work has shown that properdindeficient mice in comparison with their littermate wildtype controls exhibit an immune response which is compatible with a bias towards M2 activity [5]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call