Nikunj Shah

The role of DNA damage and repair in atherosclerosis: A review ☆ ☆☆ ★

The global burden of cardiovascular disease is increasing despite therapeutic advances in medication and interventional technologies. Accumulated deoxyribonucleic acid (DNA) damage and subsequent repair pathways are now increasingly recognised as a causal factor in the initiation and progression of atherosclerosis. These molecular alterations have been shown to occur within affected vasculature, plaque microenvironment as well as in circulating cells. The DNA damage response (DDR) pathway is reliant on post-translational modification of sensing proteins which activate a signalling cascade to repair, if possible, DNA damaged sites in response to various environmental and physiological insults. This review summarises the current evidence for DNA damage in atherosclerosis, the key steps involved in the DDR pathway, DNA repair and their subsequent effects on atherosclerotic plaques, as well as the therapeutic options in managing DNA damage-induced atherosclerosis.

MicroRNA 8059 as a marker for the presence and extent of coronary artery calcification

Objective MicroRNAs (miRNAs) may serve as potential biomarkers in a variety of pathologies. The aim of this study was to determine whether miRNAs could serve as blood-based markers of isolated coronary artery calcification (CAC) defined as CAC in the absence of an underlying metabolic abnormality. Methods 24 age-matched and sex-matched patients who had been referred for elective CT coronary calcium score and angiography as part of investigation for cardiac chest pain were recruited. Peripheral venesection was performed and an Agatston calcium score was derived from the CT coronary angiogram using default software. RNA was extracted using the LeukoLOCK Total RNA Isolation System for Toray’s microarray analysis and quantitative reverse transcription PCR (qRT-PCR). Results The patients were well matched for age, sex and conventional risk factors for coronary artery disease. Microarray analysis identified lower expression of miRNA-138-2-3p, miRNA-1181, miRNA-6816-3p and miRNA-8059 in patients with coronary artery calcium score (CACS)=0 vs CACS>100. qRT-PCR confirmed significant downregulation of miRNA-8059 in patients with CACS>100 (CACS=0 vs CACS>100; P=0.03). Conclusion miRNA-8059 may serve as a peripheral blood-based biomarker for the presence of CAC, as well as provide a platform for studying the pathophysiological basis of isolated CAC. Trial registration number NCT01992848; Results.

9 Micrornas Represent Novel Biological Markers of Coronary Artery Calcification

Introduction Conventional risk stratification fails to identify many individuals presenting with major adverse cardiovascular events (MACE). Coronary artery calcification (CAC) is a powerful independent predictor of MACE however its use is limited by radiation and expense. MicroRNAs are non-coding RNAs that regulate transcription and their differential expression is acknowledged to be a hallmark of a number of diseases. We aim to determine if a peripheral blood-based microRNA profile is predictive of the presence and extent of CAC in humans. Methods Study patients met the following inclusion criteria: attendance for elective cardiac computed tomography; age 18–65 years; no history of coronary artery disease, cardiomyopathy or tachyarrhythmia; normal renal function; no history of diabetes mellitus; no autoimmune disease; no infection; no malignancy. Peripheral venesection was performed and an Agatston score was derived using default software. RNA was extracted using the LeukoLOCK Total RNA Isolation System and stored at –80oC until Toray’s microarray analysis was undertaken. Results 24 participants were recruited (mean age 54 years; 67% male) and divided into the following categories: [CAC score 0] n = 6; [CAC score 1–10] n = 6; [CAC score 11–100] n = 6; [CAC score > 100] n = 6. Groups were matched according to their baseline characteristics; Table 1. The Student’s t-test was performed between groups. MiR-1181 was significantly down-regulated in all case groups compared to controls: [CAC 1–10] effect size (ES) = 1.76, p = 0.012; [CAC 11–100] ES = 1.74, p = 0.013; [CAC > 100] ES = 3.86, p < 0.01. Furthermore miR-138-2-3p, miR-6816-3p and miR-8059 were expressed less in those with a CAC score > 100 compared to controls (ES = 3, p < 0.001; ES = 2.87, p < 0.001; ES = 2.6, p = 0.001 respectively); Figure 1. Abstract 9 Table 1 Patient baseline characteristics by group Abstract 9 Figure 1 A heatmap of expression for miR-6816-3p, miR-1181, miR-138-2-3p and miR-8059. The expression range ‘low-moderate-high’ is indicated by the colour range ‘blue-white-red’ Conclusions Human blood-based miRNA-1181 appears to predict the presence and extent of CAC. Likewise miRNAs miR-138-2-3p, miR-6816-3p and miR-8059 are differentially expressed in patients with high CAC scores. We plan to validate these findings using quantitative real-time PCR and to test these results in a prospective cohort. Ultimately miRNAs could act as a biomarker for MACE and identifying their associated molecular pathways may explain the mechanisms underpinning CAC.