title: Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations.
abstract: 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.
authors.affiliation: Department of Biophysics, Biological Faculty, Moscow State University, 119991 Moscow, Russia; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia. Electronic address: a.h.opexob@gmail.com.
authors.forename: A N
authors.initials: AN
authors.lastname: Orekhov
authors.affiliation: Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. Electronic address: zhelankin.andrey@gmail.com.
authors.forename: A V
authors.initials: AV
authors.lastname: Zhelankin
authors.affiliation: Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. Electronic address: kirruccha@rambler.ru.
authors.forename: K I
authors.initials: KI
authors.lastname: Kolmychkova
authors.affiliation: Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia. Electronic address: kymitrofanov@gmail.com.
authors.forename: K Yu
authors.initials: KY
authors.lastname: Mitrofanov
authors.affiliation: Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. Electronic address: marykumy@gmail.com.
authors.forename: M V
authors.initials: MV
authors.lastname: Kubekina
authors.affiliation: Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium. Electronic address: kate.ivanov@gmail.com.
authors.forename: E A
authors.initials: EA
authors.lastname: Ivanova
authors.affiliation: Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. Electronic address: igor.sobenin@gmail.com.
authors.forename: I A
authors.initials: IA
authors.lastname: Sobenin
mesh_terms: D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology*; D059168:Carotid Intima-Media Thickness; D002469:Cell Separation; D004272:DNA, Mitochondrial / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics*; D009000:Monocytes / Q000276:immunology*; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial
keywords: Activation; Atherosclerosis; Cytokine; Mitochondrial DNA mutations; Monocyte