Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis

Peer reviewe

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Changes of mitochondria in atherosclerosis : possible determinant in the pathogenesis of the disease

Electron-microscopic analysis of atherosclerotic lesions demonstrated a high variability in the ultra-structural appearance of mitochondria in human aortic atherosclerotic lesions compared with the appearance of mitochondria in the normal parts of the aortic intima. This prompted us to suggest that the structural variations in the appearance of mitochondria might reflect the existence of somatic mutations in the human mitochondrial genome which could be a determinant of atherosclerosis. To test this hypothesis, we have compared the levels of heteroplasmy for several mitochondrial mutations previously proposed to be associated with different types of atherosclerotic lesions. The homogenates of unaffected aortic intimae and lipofibrous plaques of 12 male aortas were compared to reveal the average level of heteroplasmy for A1555G, C3256T, T3336T, G12315A, G14459A, and G15059A mutations of human mitochondrial genome. It has been shown at least four mutations of mitochondrial genome, namely, A1555G in MT-RNR1 gene, C3256T in MT-TL1 gene, G12315A in MT-TL2 gene, and G15059A in MT-CYB gene have significantly higher prevalence and mean value in lipofibrous plaques as compared to non-atherosclerotic intima, and therefore are associated with atherosclerosis. Somatic mutations in the human mitochondrial genome might play a role in the development of atherosclerosis. The mitochondrial mutations observed in our study should encourage further exploration of the concept that mitochondrial DNA heteroplasmy might be used as a biomarker of atherogenesis

Mitochondrial mutations are associated with atherosclerotic lesions in the human aorta

Somatic mutations of the human mitochondrial genome can be a possible determinant of atherosclerosis. To test this possibility, forty mitochondrial mutations were analyzed in the present study in order to see which of these mutations might be associated with atherosclerosis. Ten mitochondrial mutations belonging to mitochondrial genes MT-RNR1 (rRNA 12S); MT-TL1 (tRNA-Leu, recognizes UUR); MT-TL2 (tRNA-Leu, recognizes CUN); MT-ND1, MT-ND2, MT-ND5, and MT-ND6 (subunits 1, 2, 5, and 6, respectively, of NADH dehydrogenase); and MT-CYB (cytochrome b) were potentially associated with atherosclerosis. From 29% (2 of 7 aortic samples) upto 86% (6 of 7 aortic samples) of aortic samples had a significant difference between atherosclerotic plaques and unaffected tissue, with the respect to the level of heteroplasmy for each mutation. Further, the homogenates of affected and normal intimae of 22 aortas were compared to reveal the average level of heteroplasmy for the above-mentioned 10 mutations. For five mutations, the mean level of heteroplasmy was significantly different in atherosclerotic intimal homogenates in comparison with the unaffected tissue. These mutations were A1555G, C3256T, T3336C, G13513A, and G15059A. Thus, it was demonstrated that at least five mitochondrial mutations occurring in MT-RNR1, MT-TL1, MT-ND2, MT-ND5, and MT-CYB genes are associated with atherosclerosis

Is There a Relationship between Adverse Pregnancy Outcomes and Future Development of Atherosclerosis?

Cardiovascular disease is one of the main death causes globally. Effective cardiovascular risk management requires a thorough understanding of the mechanisms underlying the disorder. Establishing early markers of the disease allows a timely intervention and prevention of further atherosclerosis development. Multiple studies confirm the correlation between pregnancy disorders and cardiovascular disease in the postpartum period. Moreover, over 30% of women experience adverse pregnancy outcomes. Thus, the examination of the links between these conditions and atherosclerotic cardiovascular disease may help to identify gender-specific risk factors. In this review, we will explore the association between several adverse pregnancy outcome conditions and atherosclerosis. The current analysis is based on the data from several recent studies on the mechanisms behind gestational diabetes, hypertensive disorders of pregnancy, miscarriages, and stillbirths and their implications for the female cardiovascular system

Quantitative analysis of the expression of caspase 3 and caspase 9 in different types of atherosclerotic lesions in the human aorta

The existing data on apoptotic processes in human atherosclerotic lesions is insufficient and is often contradictory. This study was undertaken to evaluate the levels of the expression of key apoptosis-related genes, namely, caspase 3 (CASP3) and caspase 9 (CASP9) in the normal (non-atherosclerotic) intima of the human aorta in comparison with those in different types of atherosclerotic lesions. Twenty-five autopsy samples of thoracic aorta were examined by polymerase chain reaction (PCR) analysis. The study revealed that the expressions of CASP3 and CASP9 genes were changed in different types of atherosclerotic lesions in course of the progression of the disease, but not in a unanimous way. The mRNA expression of CASP3 was found to be steadily decreasing with the progression of atherosclerosis while the expression of CASP9 showed a pattern which can be described as a "bell-shaped" relationship between gene mRNA expression and the type of atherosclerotic lesion, with the maximum being observed in fatty streaks. The fall in CASP3 expression may be associated with cellular senescence as well as with the domination of necrotic processes in atherosclerotic lesions, as shown by electron microscopic analysis. Our study provides novel quantitative data on the expression of CASP3 and CASP9 genes in different atherosclerotic lesions in the human aorta and thus, might assist in better understanding of the processes occurring during the development of lesions in human atherogenesis

The Neuroimmune Role of Intestinal Microbiota in the Pathogenesis of Cardiovascular Disease

Currently, a bidirectional relationship between the gut microbiota and the nervous system, which is considered as microbiota-gut-brain axis, is being actively studied. This axis is believed to be a key mechanism in the formation of somatovisceral functions in the human body. The gut microbiota determines the level of activation of the hypothalamic–pituitary system. In particular, the intestinal microbiota is an important source of neuroimmune mediators in the pathogenesis of cardiovascular disease. This review reflects the current state of publications in PubMed and Scopus databases until December 2020 on the mechanisms of formation and participation of neuroimmune mediators associated with gut microbiota in the development of cardiovascular disease

Quantitative Assessment of Heteroplasmy of Mitochondrial Genome: Perspectives in Diagnostics and Methodological Pitfalls

The role of alterations of mitochondrial DNA (mtDNA) in the development of human pathologies is not understood well. Most of mitochondrial mutations are characterized by the phenomenon of heteroplasmy which is defined as the presence of a mixture of more than one type of an organellar genome within a cell or tissue. The level of heteroplasmy varies in wide range, and the expression of disease is dependent on the percent of alleles bearing mutations, thus allowing consumption that an upper threshold level may exist beyond which the mitochondrial function collapses. Recent findings have demonstrated that some mtDNA heteroplasmic mutations are associated with widely spread chronic diseases, including atherosclerosis and cancer. Actually, each etiological mtDNA mutation has its own heteroplasmy threshold that needs to be measured. Therefore, quantitative evaluation of a mutant allele of mitochondrial genome is an obvious methodological challenge, since it may be a keystone for diagnostics of individual genetic predisposition to the disease. This review provides a comprehensive comparison of methods applicable to the measurement of heteroplasmy level of mitochondrial mutations associated with the development of pathology, in particular, in atherosclerosis and its clinical manifestations

Analysis of mitochondrial DNA heteroplasmic mutations A1555G, C3256T, T3336C, C5178A, G12315A, G13513A, G14459A, G14846A and G15059A in CHD patients with the history of myocardial infarction

The present study was undertaken in order to advance our earlier studies directed to define genetic risk of atherosclerotic vascular lesion development on a base on the analysis of sets of mutational load relevant to the mitochondrial genome mutations. A comparative evaluation of the two study participants’ populations (that included coronary heart disease (CHD) patients who underwent myocardial infarction and apparently healthy donors with no clinical manifestations of coronary heart disease) on heteroplasmy levels of nine mutations of the mitochondrial genome (A1555G, C3256T, T3336C, С5178А, G12315A, G13513A, G14459A, G14846А and G15059A) that were shown previously to be associated with risk factors for atherosclerosis was performed. Close associations with the risk of cardiovascular disease were confirmed for mutation C3256T (gene MT-TL1), G12315A (gene MT-TL2), G13513A (gene MT-ND5) and G15059A (gene MT-CYB) by RT-PCR

Association of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertension

AIM: To examine whether the heteroplasmy level for 15059G>A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Atherosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G>A mutation occurring in the coding region of cytochrome b gene (MT-CYB ) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G>A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G>A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G>A heteroplasmy correlated both with age (r = 0.331, P A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G>A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G>A heteroplasmy level were found to have significantly higher age (P A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G>A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G>A mutation heteroplasmy with essential hypertension