High levels of high-density lipoprotein (HDL) cholesterol inhibit the formation of abdominal aortic aneurysm (AAA), findings from experimental mouse models suggest.
This finding could potentially explain why patients with AAA have lower concentrations of HDL, say Gillian Cockerill (Cardiovascular Sciences Centre, London, UK) and colleagues in Arteriosclerosis, Thrombosis, and Vascular Biology.
They found that elevated HDL cholesterol before or at the time of AAA induction reduced AAA formation in both the angiotensin II-induced hypercholesterolemic and CaCl2-induced normocholesterolemic mouse model of AAA, but had no significant effect on early ruptures.
"The mechanism whereby elevation of HDL is able to inhibit induction and growth of aneurysms, but not rupture, requires further investigation," Cockerill and team say.
Analysis of protein lysates from specific aortic segments revealed site-specific effects of HDL cholesterol on early signal transduction and cellular attrition. Indeed, the researchers found that HDL reduced activation of extracellular signal-related kinases 1/2 in the suprarenal segment, while having no effect on p38 mitogen-associated protein kinase activation in any aortic segment and inhibiting c-Jun N-terminal kinase activation in all aortic segments.
In addition, HDL elevation inhibited angiotensin II-induced apoptosis, while inducing autophagy in the suprarenal segment of the aorta.
The authors say that theirs is the first study to describe a site-specific imbalance between apoptosis and autophagy, "which may explain the localization of lesion formation."
Using Illumina gene array profiling, Cockerill et al also found that among 155 genes significantly modulated by increasing plasma concentration of reconstituted discoidal HDL, 26% of the top 30 upregulated genes are involved in the synthesis, cross-linking, and degradation of extracellular matrix, known to be essential to the pathogenesis of abdominal aneurysm.
"These data provide support for the idea that pharmacological modulation of plasma HDL could be of therapeutic benefit for the treatment of AAA and may also add to our understanding of site specificity," they conclude.
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