Mitochondrial microRNAs: New Emerging Players in Vascular Senescence and Atherosclerotic Cardiovascular Disease.

MicroRNAs (miRNAs) are small non-coding RNAs that play an important role by controlling gene expression in the cytoplasm in almost all biological pathways. Recently, scientists discovered that miRNAs are also found within mitochondria, the energy-producing organelles of cells. These mitochondrial miRNAs, known as mitomiRs, can originate from the nuclear or mitochondrial genome, and they are pivotal in controlling mitochondrial function and metabolism. New insights indicate that mitomiRs may influence key aspects of the onset and progression of cardiovascular disease, especially concerning mitochondrial function and metabolic regulation. While the importance of mitochondria in cardiovascular health and disease is well-established, our understanding of mitomiRs' specific functions in crucial biological pathways, including energy metabolism, oxidative stress, inflammation, and cell death, is still in its early stages. Through this review, we aimed to delve into the mechanisms of mitomiR generation and their impacts on mitochondrial metabolic pathways within the context of vascular cell aging and atherosclerotic cardiovascular disease. The relatively unexplored field of mitomiR biology holds promise for future research investigations, with the potential to yield novel diagnostic tools and therapeutic interventions.

Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells.

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 µM and 200 µM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = -0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = -0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere-mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.

Ultrastructural and Molecular Investigation on Peripheral Leukocytes in Alzheimer's Disease Patients.

Thriving literature underlines white blood cell involvement in the inflammatory processes of Alzheimer's Disease (AD). Among leukocytes, lymphocytes have been considered sentinels of neuroinflammation for years, but recent findings highlighted the pivotal role of neutrophils. Since neutrophils that infiltrate the brain through the brain vascular vessels may affect the immune function of microglia in the brain, a close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and the immunological aftermaths that follow. This study aimed to observe how peripheral leukocyte features change at different stages of AD to identify potential molecular markers when the first features of pathological neurodegeneration arise. For this purpose, the examined patients were divided into Mild Cognitive Impairment (MCI) and severely impaired patients (DAT) based on their Cognitive Dementia Rating (CDR). The evaluation of the neutrophil-to-lymphocytes ratio and the morphology and function of leukocytes showed a close relationship between the ultrastructural and the molecular features in AD progression and suggested putative markers for the early stages of the disease.

Gut Microbiota and Sex Hormones: Crosstalking Players in Cardiometabolic and Cardiovascular Disease.

The available evidence indicates a close connection between gut microbiota (GM) disturbance and increased risk of cardiometabolic (CM) disorders and cardiovascular (CV) disease. One major objective of this narrative review is to discuss the key contribution of dietary regimen in determining the GM biodiversity and the implications of GM dysbiosis for the overall health of the CV system. In particular, emerging molecular pathways are presented, linking microbiota-derived signals to the local activation of the immune system as the driver of a systemic proinflammatory state and permissive condition for the onset and progression of CM and CV disease. We further outline how the cross-talk between sex hormones and GM impacts disease susceptibility, thereby offering a mechanistic insight into sexual dimorphism observed in CVD. A better understanding of these relationships could help unravel novel disease targets and pave the way to the development of innovative, low-risk therapeutic strategies based on diet interventions, GM manipulation, and sex hormone analogues.

Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression.

The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H2O2. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription.

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer's Disease Progression.

Alzheimer's disease (AD) is the leading cause of dementia, but the pathogenetic factors are not yet well known, and the relationships between brain and systemic biochemical derangements and disease onset and progression are unclear. We aim to focus on blood biomarkers for an accurate prognosis of the disease. We used a dataset characterized by longitudinal findings collected over the past 10 years from 90 AD patients. The dataset included 277 observations (both clinical and biochemical ones, encompassing blood analytes encompassing routine profiles for different organs, together with immunoinflammatory and oxidative markers). Subjects were grouped into four severity classes according to the Clinical Dementia Rating (CDR) Scale: mild (CDR = 0.5 and CDR = 1), moderate (CDR = 2), severe (CDR = 3) and very severe (CDR = 4 and CDR = 5). Statistical models were used for the identification of potential blood markers of AD progression. Moreover, we employed the Pathfinder tool of the Reactome database to investigate the biological pathways in which the analytes of interest could be involved. Statistical results reveal an inverse significant relation between four analytes (high-density cholesterol, total cholesterol, iron and ferritin) with AD severity. In addition, the Reactome database suggests that such analytes could be involved in pathways that are altered in AD progression. Indeed, the identified blood markers include molecules that reflect the heterogeneous pathogenetic mechanisms of AD. The combination of such blood analytes might be an early indicator of AD progression and constitute useful therapeutic targets.

Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease.

Telomere dysfunction is implicated in vascular aging and shorter leucocyte telomeres are associated with an increased risk of atherosclerosis, myocardial infarction, and heart failure. Another pathophysiological mechanism that explains the causal relationship between telomere shortening and atherosclerosis development focuses on the clonal hematopoiesis of indeterminate potential (CHIP), which represents a new and independent risk factor in atherosclerotic cardiovascular diseases. Since telomere attrition has a central role in driving vascular senescence, understanding telomere biology is essential to modulate the deleterious consequences of vascular aging and its cardiovascular disease-related manifestations. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for "TElomeric Repeat-containing RNA", actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the multiple biological functions of TERRA remain to be largely elucidated. In particular, the role of TERRA in vascular biology is surprisingly unknown. In this review, we discuss the current knowledge of TERRA and its roles in telomere biology. Additionally, we outline the pieces of evidence that exist regarding the relationship between TERRA dysregulation and disease. Finally, we speculate on how a comprehensive understanding of TERRA transcription in the cardiovascular system may provide valuable insights into telomere-associated vascular aging, offering great potential for new therapeutic approaches.

Mitochondria-Targeted Drug Delivery in Cardiovascular Disease: A Long Road to Nano-Cardio Medicine.

Cardiovascular disease (CVD) represents a major threat for human health. The available preventive and treatment interventions are insufficient to revert the underlying pathological processes, which underscores the urgency of alternative approaches. Mitochondria dysfunction plays a key role in the etiopathogenesis of CVD and is regarded as an intriguing target for the development of innovative therapies. Oxidative stress, mitochondrial permeability transition pore opening, and excessive fission are major noxious pathways amenable to drug therapy. Thanks to the advancements of nanotechnology research, several mitochondria-targeted drug delivery systems (DDS) have been optimized with improved pharmacokinetic and biocompatibility, and lower toxicity and antigenicity for application in the cardiovascular field. This review summarizes the recent progress and remaining obstacles in targeting mitochondria as a novel therapeutic option for CVD. The advantages of nanoparticle delivery over un-targeted strategies are also discussed.