Microplastics induce mitochondrial dysfunction and accelerate cardiovascular pathogenesis.

Cardiovascular disease (CVD) remains a global health challenge, primarily due to atherosclerosis, which leads to conditions such as coronary artery disease, cerebrovascular disease, and peripheral arterial disease. Mitochondrial dysfunction initiates endothelial dysfunction, a key contributor to CVD pathogenesis, as well as triggers the accumulation of reactive oxygen species (ROS), energy stress, and cell death in endothelial cells, which are crucial for atherosclerosis development. This review explores the role of PTEN-induced protein kinase 1 (PINK1) in mitochondrial quality control, focusing on its significance in cardiovascular health. PINK1 plays a pivotal role in mitophagy (selective removal of damaged mitochondria), contributing to the prevention of CVD progression. PINK1-mediated mitophagy also affects the maintenance of cardiomyocyte homeostasis in ischemic heart disease, thus mitigating mitochondrial dysfunction and oxidative stress, as well as regulates endothelial health in atherosclerosis through influencing ROS levels and inflammatory response. We also investigated the role of PINK1 in vascular smooth muscle cells, emphasizing on its role in apoptosis and atherosclerosis. Dysfunctional mitophagy in these cells accelerates cellular senescence and contributes to adverse effects including plaque rupture and inflammation. Mitophagy has also been explored as a potential therapeutic target for vascular calcification, a representative lesion in atherosclerosis, with a focus on lactate-induced mechanisms. Finally, we highlight the current research and clinical trials targeting mitophagy as a therapeutic avenue for CVD.

Platelet abnormalities are well-recognized complications of diabetes mellitus. Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in diabetes mellitus. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in platelets in diabetes mellitus is unknown. Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase activation and subsequent reactive oxygen species production lead to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage, and rupture by sequestration of the antiapoptotic protein Bcl-xL. In a glucose dose-dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation, and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, aldose reductase activation, reactive oxygen species production, and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are 2 distinct states that depend on the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model. Aldose reductase contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for thrombotic complications in diabetes mellitus.

The Na +/K +-ATPase as [K +] o sensor: Role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids

Introduction: Cardiovascular diseases remain the leading cause of mortality worldwide, and its incidence is increasing with the population aging. A growing number of studies indicate that vitamin D deficiency, which is common in the global population, may play an important role in the pathogenesis of cardiovascular diseases by influencing inflammatory processes, oxidative stress, the renin-angiotensin-aldosterone system, calcium-phosphate metabolism, and endothelial function. As a result, vitamin D has become the subject of intensive analysis regarding its potential impact on the prognosis of patients with hypertension, heart failure, atherosclerosis, diabetes, and arrhythmias. Aim of the study: The aim of the study was to present the current state of knowledge on the association between vitamin D deficiency and the risk and management of cardiovascular diseases, as well as to evaluate the role of vitamin D supplementation in the prevention and treatment of these diseases. Material and methods: This paper provides a review of the literature including current experimental, observational, and randomized controlled studies on vitamin D metabolism, the significance of 25(OH)D deficiency, pathophysiological mechanisms, and the effects of supplementation. Included publications present the impact of vitamin D on endothelial function, oxidative stress, atherosclerosis, the neurohormonal system, glucose metabolism, and the risk of arrhythmia. Results and Conclusions: A review of the literature indicates that vitamin D deficiency is associated with an increased risk of hypertension, heart failure, type 2 diabetes, atherosclerosis, and cardiac arrhythmias, including atrial fibrillation. The mechanisms of this effect include the action of VDR receptors in cardiomyocytes and vascular cells, modulation of the inflammatory response, reduction of oxidative stress, and regulation of the RAA system. Observational data suggest potential benefits of vitamin D supplementation, especially in high-risk groups, but large randomized clinical trials do not conclusively confirm that routine vitamin D administration reduces the number of major cardiovascular events in the general population. It is therefore necessary to individualize supplementation and conduct further well-designed studies to identify populations that may benefit most from therapy.

Selective autophagy of mitochondria, known as mitophagy, is a major quality control pathway in the heart that is involved in removing unwanted or dysfunctional mitochondria from the cell. Baseline mitophagy is critical for maintaining fitness of the mitochondrial network by continuous turnover of aged and less-functional mitochondria. Mitophagy is also critical in adapting to stress associated with mitochondrial damage or dysfunction. The removal of damaged mitochondria prevents reactive oxygen species-mediated damage to proteins and DNA and suppresses activation of inflammation and cell death. Impairments in mitophagy are associated with the pathogenesis of many diseases, including cancers, inflammatory diseases, neurodegeneration, and cardiovascular disease. Mitophagy is a highly regulated and complex process that requires the coordination of labeling dysfunctional mitochondria for degradation while simultaneously promoting de novo autophagosome biogenesis adjacent to the cargo. In this review, we provide an update on our current understanding of these steps in mitophagy induction and discuss the physiological and pathophysiological consequences of altered mitophagy in the heart.

Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction.

Role of IL-37 in Cardiovascular Disease Inflammation

Highlights HOTAIR, a long noncoding RNA, plays a role in the regulation of proteins involved in the pathogenesis of cardiovascular disease. Furthermore, it has been identified as a biomarker of this type of disease. Several factors and cells contribute to atherosclerosis, a progressive disease. However, the prognosis of HOTAIR in this disease varies depending on the path in which it plays a role. For this condition, there is no single prognosis to consider.

Parkin-mediated mitophagy is involved in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC)

The redox status is determined by the balance between the production of reactive oxygen species (ROS) and their removal by the antioxidant defense system. Mitochondria, the center of oxidative metabolism and the principal site of ROS production, are crucial in health and also in the pathogenesis of many diseases. Mitochondrial dysfunction, resulting in a vicious cycle contributing to cellular damage and consequent cell death, has been proven to play a critical role in the pathogenesis of cardiovascular diseases. Previous studies have shown that mitochondrial transfer in cells plays a crucial role in regulating cardiovascular system development and maintaining normal tissue homeostasis. We review and evaluate in this chapter the evidence for mitochondrial dysfunction as a consequence of stress exposure and a contributing factor to cardiovascular diseases.

Cellular senescence is a complex, dynamic process consisting of the irreversible arrest of growth and gradual deterioration of cellular function. Endothelial senescence affects the cell’s ability to repair itself, which is essential for maintaining vascular integrity and leads to the development of endothelial dysfunction, which has an important role in the pathogenesis of cardiovascular diseases. Senescent endothelial cells develop a particular, senescence-associated secretory phenotype (SASP) that detrimentally affects both surrounding and distant endothelial cells, thereby facilitating the ageing process and development of age-related disorders. Recent studies highlight the role of endothelial senescence and its dysfunction in the pathophysiology of several age-related diseases. MicroRNAs are small noncoding RNAs that have an important role in the regulation of gene expression at the posttranscriptional level. Recently, it has been discovered that miRNAs could importantly contribute to endothelial cell senescence. Overall, the research focus has been shifting to new potential mechanisms and targets to understand and prevent the structural and functional changes in ageing senescent endothelial cells in order to prevent the development and limit the progression of the wide spectrum of age-related diseases. The aim of this review is to provide some insight into the most important pathways involved in the modulation of endothelial senescence and to reveal the specific roles of several miRNAs involved in this complex process. Better understanding of miRNA’s role in endothelial senescence could lead to new approaches for prevention and possibly also for the treatment of endothelial cells ageing and associated age-related diseases.

See related article, pages 1032–1039 Hypertension, diabetes, and atherosclerosis are three diseases responsible for the majority of cardiovascular morbidity in humans. Not only are they independent risk factors, but they clearly potentiate and complement each other in the pathogenesis of cardiovascular disease. The first manifestation of end-organ damage in these diseases is the vascular remodeling of small (resistance) and large (conductance), and this precedes the development of cardiac hypertrophy, renal insufficiency or stroke.1 This vascular remodeling is characterized by hyperplasia, hypertrophy, and apoptosis of smooth muscle cells (SMCs) and vascular fibrosis, caused by increased extracellular matrix deposition of total collagen, and changes in ratio of type I/III collagen, fibronectin, and proteoglycans.1 Angiotensin II (Ang II) has recently emerged as a key mediator of vascular fibrosis (sclerosis) both in humans and animal models of hypertension because of its pleiotropic effects of SMCs, fibroblasts, and inflammatory cells. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) diminish cardiac hypertrophy and vascular fibrosis in animal models of hypertension.1,2 In human clinical trials of hypertension, ARBs reverse vascular remodeling in resistance arteries and new incidence of strokes more potently than any other antihypertensive agents (beta-blockers or calcium channel blockers), despite similar reduction in blood pressure.3,4 This provides strong evidence that targeting the mechanisms involved in arterial remodeling process may provide the key in preventing the long-term consequences of hypertension or atherosclerosis in humans. However, deciphering the intimate mechanisms of in vivo vascular remodeling has become very complex because of enormous reciprocal interactions between Ang II and other growth factors. Ang II exerts its effects not only by activating its specific receptors, but also by transactivating other growth factor receptors such as epidermal growth factor …

This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

In the pathogenesis of cardiovascular diseases (CVDs), ferroptosis is increasingly implicated as a key mechanism. This iron-driven, regulated cell death is characterized by the accumulation of lipid peroxides and a deficiency in glutathione. This comprehensive review delineates the molecular underpinnings of ferroptosis—encompassing dysregulated iron metabolism, GPX4 inactivation, and lipid peroxidation—and elucidates its pivotal role in a spectrum of cardiac pathologies. Notably, ferroptosis contributes to oxidative stress, mitochondrial dysfunction, and inflammatory responses, accelerating myocardial damage and functional decline. Emerging evidence indicates that several drugs targeting the ferroptosis pathway including iron chelators, antioxidants, and small-molecule inhibitors such as ferrostatin-1 and liproxstatin-1, demonstrate cardioprotective effects in preclinical models. However, translational challenges remain, including context-dependent roles of regulators like p53 and AMPK, and the need for organelle-specific interventions. This review synthesizes current knowledge and proposes ferroptosis as a promising target for precision medicine in CVDs, urging further research into biomarkers and combination therapies to mitigate the global burden of cardiovascular morbidity and mortality.

Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin