Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations.

We have recently evaluated the susceptibility of circulating monocytes to pro- and anti-inflammatory activation comparing samples from healthy individuals and patients with asymptomatic carotid atherosclerosis. Surprisingly, we found a dramatic individual difference in susceptibility to activation between monocytes isolated from the blood of different subjects, regardless of the presence or absence of atherosclerosis. In the present study the monocyte susceptibility to pro-inflammatory activation was evaluated in comparison with mitochondrial DNA mutations that have previously been shown to correlate with the degree of carotid atherosclerosis assessed by intima-media thickness. Among the mutations associated with atherosclerosis were both homoplasmic (absence or presence of the mutation) or heteroplasmic (different proportions of mutant allele). It was found that two homoplasmic mutations, A1811G and G9477A, tended to correlate with the degree of monocyte susceptibility to activation. At the same time, the mutation G9477A inversely correlated with the degree of monocyte activability, that is, the mutation was more prevalent in monocytes with a low degree of activability. We have found that at least three heteroplasmic mutations of mtDNA (G14459A, A1555G, G12315A) earlier known to be associated with human atherosclerosis, also correlate with proinflammatory activation of circulating human monocytes. We suggest that some mutations can cause mitochondrial dysfunction, which in turn may lead to changes of macrophage activities in atherosclerosis.

[Analysis of mitochondrial haplogroups in persons with subclinical atherosclerosis based on high-throughput mtDNA sequencing].

Genetic predisposition plays an important role among other risk factors in multifactorial socially significant diseases such as atherosclerosis and its clinical manifestations. This pilot study was aimed to identify the relationship between the type of mitochondrial haplogroup and the risk of subclinical atherosclerosis in humans. For accurate detection of mitochondrial haplogroups, high-throughput sequencing of the mitochondrial genome using the Roche 454 technology was carried out. The results have shown that in Russian population, the belonging to haplogroup H is associated with an increased risk of atherosclerosis, but belonging to haplogroups T and U--with reduced risk. The data obtained can be used to assess individual risk of atherosclerosis and for further studies on the role of mitochondrial genome mutations in the development of atherosclerosis and its clinical manifestations.