Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr−/− mice

Abstract

Background and Aims High blood pressure and reduced aortic compliance are associated with increased atherosclerotic plaque accumulation in humans. Animal studies support these associations, but additional factors, such as fragmented elastic fibers, are present in most previous animal studies. Elastin heterozygous (Eln+/−) mice have high blood pressure and reduced aortic compliance, with no evidence of elastic fiber fragmentation and represent an appropriate model to directly investigate the effects of these factors on atherosclerosis Methods and Results Eln+/− and Eln+/+ mice were crossed with low density lipoprotein receptor knockout (Ldlr−/−) and wild-type (Ldlr+/+) mice and fed normal or Western diet (WD) for 16 weeks. We hypothesized that on WD, Eln+/−Ldlr−/− mice with high blood pressure and reduced aortic compliance would have increased atherosclerotic plaque accumulation compared to Eln+/+Ldlr−/− mice. We measured serum cholesterol and cytokine levels, blood pressure, aortic compliance, and plaque accumulation. Contrary to our hypothesis, we found that on WD, Eln+/−Ldlr−/− mice do not have increased plaque accumulation compared to Eln+/+Ldlr−/− mice. At the aortic root, there are no significant differences in plaque area between Eln+/−Ldlr−/− and Eln+/+Ldlr−/− mice on WD (p = .89), while in the ascending aorta, Eln+/−Ldlr−/− mice on WD have 29% less normalized plaque area than Eln+/+Ldlr−/− mice on WD (p = 0.009). Conclusion Using an atherogenic mouse model, we conclude that increased blood pressure and reduced aortic compliance are not direct causes of increased aortic plaque accumulation. We propose that additional insults, such as fragmentation of elastic fibers, are necessary to alter plaque accumulation.

Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12

“…10), we note complementary findings by others demonstrating a direct relationship between increased arterial stiffness and increased atherosclerosis in atheroprone mice (49)(50)(51)(52). Two recent reports using heterozygous expression of elastin indicate that increased arterial stiffness likely accelerates (rather than increases the maximal amount of) lesion burden and that this effect may be site specific and involve nonmechanical factors such as blood pressure and circulating soluble factors (49,53).…”

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1

“…Van Herck et al modified ApoE−/− knockout mice to disrupt elastin formation and found that atherosclerosis formed in stiffened arteries and that more arterial stiffness was associated with more atherosclerotic plaque 47 . However recently, the direct relationship between stiffness and atherosclerosis has been called into question by the Wagensiel group using a combination of elastin deficient and Ldlr knockout mice 48 . Prior work in the Jo lab has demonstrated that combining partial carotid ligation with a high fat diet in ApoE−/− mice led to rapid atherosclerotic plaque formation in d-flow regions 24 , and given the model and our findings in this paper, it is highly likely that stiffening preceded these plaques.…”

Exposure of tropoelastin to peroxynitrous acid gives high yields of nitrated tyrosine residues, di-tyrosine cross-links and altered protein structure and function

“…Disorganized elastic fibre composition and reduced artery wall integrity (as evidenced by a greater extent of fragmented internal elastic laminae) is a known feature in cardiovascular disease in both humans [37] and many mouse strains [90] (though not apparently elastin heterozygous knockout mice [91]), and together these data suggest that this might be due to either modification by ONOOH of newly-synthesised TE, which then does not incorporate (or incorporates incorrectly) into existing fibres, or ONOOH-induced changes to mature elastin.…”