ABCC6 deficiency promotes dyslipidemia and atherosclerosis

Abstract

ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr−/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis

“…Nonetheless, it is known that a lack of PPi is not the only disease mechanism in PXE. Also mitochondrial dysfunction and oxidative stress, apoptosis, inflammation and dysfunctional inhibitors of calcification, such as matrix gla protein (MGP) and fetuin-A have been described to contribute to the elastic fiber calcification in PXE patients, cell- and animal models ( Uitto et al, 2010 ; Hosen et al, 2014 ; Brampton et al, 2021 ).…”

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…Thus, understanding how ABCC6 (and NPP1) influences the homeostasis of connective tissues may one day be used to enhance tissue repair and lessen mineralization-associated morbidity and mortality in the general population. This is particularly important in light of recent reports suggesting that three of the genes in the pathway shown in Figure 1 and Figure 3 that cause ectopic calcification in PXE, GACI, and CALJA [ 6 , 8 , 9 , 10 , 11 , 17 , 18 , 20 ] have also been shown to play a role in dyslipidemia and atherosclerosis [ 93 , 94 , 222 , 223 , 224 , 225 ].…”

“…Heterozygous Abcc6 +/− mice do not develop any calcification. Similar to their human counterpart, Abcc6 −/− mice have lowered plasma PPi [ 9 , 18 ] altered lipoproteins [ 93 , 94 ], develop Randall’s plaques, and have low urinary PPi excretion [ 45 , 46 ]. These animals have been invaluable for understanding the pathobiology of PXE and to test crucial pathophysiological hypotheses [ 95 , 96 ] that in vitro approaches could partially address [ 97 ].…”

“…ABCC6 deficiency causes a broad spectrum of manifestations beyond calcification that includes vascular malformation (rete mirabile, carotid hypoplasia) [ 164 ], dyslipidemia, and atherosclerosis [ 93 , 94 ], as well as ischemic stroke [ 165 ], inflammation [ 159 ], premature cellular senescence in hepatic cells and dermal fibroblasts [ 166 , 167 ], increased infarct size, and apoptosis [ 168 ]. ATP released by ABCC6 and the nucleotides/nucleosides generated downstream by the ectonucleotidases NPP1 and CD73 regulates cellular signaling towards P2 (nucleotides) and P1 (Ado) receptors, which have a wide range of physiological influences that could well explain these other manifestations [ 124 ].…”

Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

“…The clinical appearance of PXE mainly consists of several hallmarks: formation of characteristic alterations to the skin, varying from yellowish coalescing papules to lax and redundant skin, mainly around the neck and flexural areas of the main joints [ 5 , 6 ]; in addition, the development of angioid streaks and neovascularization in the retina followed by a retinal hemorrhage and scarring, with gradual loss of central and night vision and, ultimately, blindness, are symptomatic of PXE [ 7 , 8 ]; also, early onset atherosclerosis with increased vascular occlusion and a significant burden of intermittent claudication can be signs of PXE [ 9 , 10 , 11 , 12 ]. Microvascular alterations [ 13 ] and impaired pulmonary carbon monoxide diffusion capacity are further phenotypic aspects [ 14 ].…”