Cellular and Molecular Mechanisms of Vascular Senescence and atherosclerotIC Plaque Vulnerability: the TelOmere-mitochondRIa Cross-tAlk Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 2
- 主要终点
- Telomere length
研究概览
简要总结
Chronological aging significantly contributes to structural and functional alterations in the vasculature, making it a major risk factor for atherosclerotic disease and its acute thrombotic events. DNA damage, including telomeric, non-telomeric, and mitochondrial damage, is recognized as a key initiator of vascular aging and atherogenesis. There is abundant evidence indicating the presence of oxidative DNA lesions, telomere erosion, and mitochondrial DNA damage in both experimental and human plaques, as well as in the peripheral cells of atherosclerotic patients.
It is increasingly evident that genomic instability activates signaling pathways that lead to a multitude of pathophysiological cellular and molecular changes. These changes promote inflammation, apoptosis, autophagy, and ultimately, cellular senescence, accompanied by the "senescence-associated secretory phenotype" (SASP). However, the precise mechanisms linking the DNA damage response (DDR) to senescence, SASP in vascular cells, and the pathogenesis of atherosclerosis and vulnerable atheroma are yet to be fully understood. Additional research is needed to delineate the underlying mechanisms through which mitochondrial dysfunction influences telomere length and vice versa, and how their interaction contributes to the vascular aging process. Progress in this area has the potential to uncover therapeutic targets and novel, more precise diagnostic, and prognostic indicators.
The objectives of the VICTORIA study are to examine the levels of aging-related non-coding RNA deregulation (specifically lncRNA TERRA and mitomiR) and peripheral markers of cell aging (including telomere length and mitochondrial DNA content) across the various spectra of angina pectoris (stable angina, unstable angina, NSTEMI, and STEMI). Additionally, the study aims to determine whether these markers are correlated with vulnerable plaque characteristics and major adverse cardiovascular events.
详细描述
Background - The process of chronological aging significantly contributes to structural and functional changes within the vasculature, emerging as a major risk factor for atherosclerotic disease and acute thrombotic events. Furthermore, age-related vascular deterioration can be influenced by lifestyle choices, environmental factors, and external stimuli, resulting in a gradual decline in vascular integrity and functionality.
In order, to identify potential targets for therapeutic intervention to delay or reverse the deleterious consequences of vascular aging, it is crucial to better understand the cellular and molecular mechanisms of vascular aging as well as to better define how environmental factors can accelerate the process.
Over the past decades, DNA damage-both telomeric and non-telomeric, alongside mitochondrial impairments-has emerged as a pivotal trigger in vascular aging and the development of atherosclerosis. A wealth of evidence supports the presence of oxidative DNA lesions, telomere attrition, and mitochondrial DNA damage in both experimental models and human plaque samples, as well as in the peripheral cells of individuals with atherosclerosis.
Moreover, it is increasingly evident that genomic instability can directly impact vascular cellular function by triggering signaling pathways that lead to a multitude of pathophysiological changes. These changes encompass inflammation, apoptosis, autophagy, and ultimately, cellular senescence, which is marked by the secretion of the "senescence-associated secretory phenotype" (SASP). The robust mechanistic association between DNA damage and cellular aging underscores DNA damage as a prime candidate for the primary cause of aging. Targeting DNA damage and its mechanistic correlates may provide a logical basis for the development of unified interventions aimed at mitigating age-related dysfunction and disease.
Nevertheless, the precise mechanisms linking DNA damage to SASP in vascular cells, as well as its role in the pathogenesis of atherosclerosis and vulnerable atheroma, remain elusive.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with acute coronary syndromes (unstable angina, non-ST segment elevation myocardial infarction (NSTEMI), ST segment elevation myocardial infarction (STEMI))
- •stable angina
- •non-angiographically significant coronary diseases recovered for elective diagnostic or interventional procedures
排除标准
- •cardiac shock
- •congestive heart failure
- •end stage renal diseases
- •coronary artery bypass graft
- •active cancer
研究组 & 干预措施
Patients with coronary artery diseases
Patients with acute coronary syndromes [unstable angina, non-ST segment elevation myocardial infarction (NSTEMI), ST segment elevation myocardial infarction (STEMI)] and with stable angina or non-angiographically coronary diseases recovered for elective diagnostic or interventional procedures are included in the study
干预措施: Several biomarkers (Other)
结局指标
主要结局
Telomere length
时间窗: T0, at the enrollment
Telomere length (LTL) is an index of genetic instability and senescence. LTL is measured in the DNA (extracted from blood leucocytes) by RT-PCR. Measure unit: 2\^(-ddct) or kilobases
次要结局
- Mitochondrial DNA copy number (mtDNAcn)(T0, at the enrollment)
- MitomiR(T0, at the enrollment)
- Long non-coding (lnc) RNA TERRA(T0, at the enrollment)
- pro-oxidant cytokines(T0, at the enrollment)