Microplastics and Atherosclerosis: Mechanisms.

Significance: Vascular dysfunction plays a key role in the development of arteriosclerosis, heart disease, and hypertension, which causes one-third of deaths worldwide. Vascular oxidative stress and metabolic disorders contribute to vascular dysfunction, leading to impaired vasorelaxation, vascular hypertrophy, fibrosis, and aortic stiffening. Mitochondria are critical in the regulation of metabolic and antioxidant functions; therefore, mitochondria-targeted treatments could be beneficial. Recent Advances: Vascular dysfunction is crucial in hypertension pathophysiology and exhibits bidirectional relationship. Metabolic disorders and oxidative stress contribute to the pathogenesis of vascular dysfunction and hypertension, which are associated with mitochondrial impairment and hyperacetylation. Mitochondrial deacetylase Sirtuin 3 (Sirt3) is critical in the regulation of metabolic and antioxidant functions. Clinical studies show that cardiovascular disease risk factors reduce Sirt3 level and Sirt3 declines with age, paralleling the increased incidence of cardiovascular disease and hypertension. An imbalance between mitochondrial acetylation and reduced Sirt3 activity contributes to mitochondrial dysfunction and oxidative stress. We propose that mitochondrial hyperacetylation drives a vicious cycle between metabolic disorders and mitochondrial oxidative stress, promoting vascular dysfunction and hypertension. Critical Issues: The mechanisms of mitochondrial dysfunction are still obscure in human hypertension. Mitochondrial hyperacetylation and oxidative stress contribute to mitochondrial dysfunction; however, regulation of mitochondrial acetylation, the role of GCN5L1 (acetyl-CoA-binding protein promoting acetyltransferase protein acetylation) acetyltransferase, Sirt3 deacetylase, and acetylation of specific proteins require further investigations. Future Directions: There is an urgent need to define molecular mechanisms and the pathophysiological role of mitochondrial hyperacetylation, identify novel pharmacological targets, and develop therapeutic approaches to reduce this phenomenon.

There is growing evidence that environmental risk factors (pollution and non‐chemical stressors) contribute to the global burden of cardiovascular, metabolic and mental disease. Clinical and epidemiological studies support that traffic‐associated environmental risk factors, air pollution and noise exposure, are associated with a higher risk for cardiovascular disease and significantly contribute to overall mortality. According to the results of the Lancet Commission on pollution and health, up to 9 Mio global annual deaths can be attributed to environmental pollution [Landrigan et al., Lancet 2018]. The numbers will rather increase in the future, because of increasing urbanization and continuous refinement of global exposure‐mortality models, which is supported by the recently reported global all‐cause mortality rate attributable to ambient air pollution by PM2.5 and O3 of 8.79 Mio [Lelieveld et al. and Münzel, Eur Heart J 2019]. Air pollution is obviously the leading health risk factor in the physical environment, followed by water and soil pollution with heavy metals, pesticides, other chemicals and occupational exposures. However, non‐chemical environmental health risk factors such as mental stress, light exposure, climatic changes and traffic noise are so far ignored by global health action plans. Especially for traffic noise‐related health effects there are numerous clinical and epidemiological studies reporting significant impact on cardiovascular disease. In this respect, the “exposome” concept represents a comprehensive description of lifelong exposure history and a rather novel scientific field that is now investigated more systematically. We here provide an in‐depth overview on the health effects of the external exposome, with emphasis on air pollution and traffic noise, and briefly present the actual studies on this topic. In addition, we summarize our previously published experimental research investigating effects of aircraft noise exposure in mice and men providing mechanistic insights on how noise contributes to non‐communicable disease.Support or Funding InformationThe present work was supported by the Boehringer Ingelheim Foundation “Novel and neglected risk factors” (to A.D. and T.M.).The exposome concept. The external exposome represents the sum of all environmental exposures including behavioral/ lifestyle factors. The external exposome (e.g. mental stress and environmental pollution) confer changes of the internal exposome (e.g. altered circadian clock by forward/backward shift, stress hormones, inflammation and oxidative stress) leading to health risks and disease conditions (e.g. atherosclerosis, vascular stenosis and myocardial infarction). BJP, submitted.Figure 1

Oxidative stress is thought to play a key role in the initiation and progression of cardiovascular diseases. Increased formation of reactive oxygen species (ROS) leads to endothelial dysfunction through the breakdown of NO, promotes proinflammatory gene expression, and increases the sympathetic tone. A multitude of stimuli including inflammation, cardiovascular risk factors like hypertension and cigarette smoke as well as a broad spectrum of hormones increase the systemic oxidative stress. Among these elements, however, angiotensin II is probably the most robust stimulus for ROS, which derive from Nox1- and Nox2-containing NADPH oxidases. In fact, angiotensin II activates and induces these ROS-generating enzymes. Angiotensin II is also the classic stimulus for the release of aldosterone. Interestingly, also aldosterone is an independent stimulus for vascular ROS production. This steroid hormone induces components of the NADPH oxidase like p47phox1 and p22phox and acutely increases ROS production in vascular cells2 probably through EGF receptor transactivation. Importantly, ROS may be mandatory for the deleterious effects of aldosterone in the cardiovascular system: for example, genetic deletion of the Nox2-containing NADPH oxidases prevents the aldosterone-induced interstitial fibrosis in the mouse heart.3 Furthermore, antioxidants prevent the aldosterone-induced expression of intercellular adhesion molecule-1 and MCP-1 as well as tumor …

Depression Depresses Vasodilation.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Air pollution represents a well-known environmental problem related to public health. Particulate matter (PM) is a heterogeneous mixture of chemicals, metals and soils. Its adverse effects have been correlated with particles size, being smaller particles more likely to cause a worst damage, so their study deserves more attention. Ultrafine particles (UFPs, dae < 100 nm) are short-lived particles dispersed in the environment. In Lombardy, diesel combustion and solid biomass burning are the most relevant contributors to primary UFPs emissions (15-30 nm in diameter). Toxicological studies, mainly in vitro, indicate specific effects for particles of different origin but comparative in vivo studies are scarce. PM exposure has been primarily associated to pulmonary and cardiovascular diseases through oxidative stress and inflammatory response, but recently it has been postulated that PM exposure could also be an important risk factor for neurotoxicity and could have a role in neurodegenerative diseases. In this study we analysed in BALB/c mice the effect of single and repeated intratracheal instillation of diesel (DEP) and biomass (BC) particles on respiratory, cardiovascular and central nervous systems, comparing the two different UFPs sources. The study was performed at biochemical and histopathological level. Different pro-inflammatory, cytotoxic, pro-coagulant and oxidative stress markers were measured. For the histopathological evaluation, sections of lung, heart and different parts of the central nervous system (CNS) were examined at light microscope, using standard staining tecniques and immunohistochemical methods. Inflammation was also monitored in living mice following BC or DEP intratracheal repeated administration using the FMT 1500 fluorescence tomography imaging system and the MMPSense 750 Fast probe. Our results indicate that even a single instillation of both the sources of UFPs induces a wide range of biochemical changes in the respiratory and cardiovascular systems, then confirmed by repeated instillation. In the CNS similar modifications were observed, although these were much more evident after repeated instillations. Histological examination demonstrated the presence of macrophages containing particles in the lungs after UFPs single and, more abundantly, repeated administration. However, significant changes were not observed in sections of heart and CNS. DEP was more effective in inducing oxidative stress and inflammation compared to BC.

Introduction

In the past century, the lifespan of the human population has dramatically increased to the 80s, but it is hindered by a limited health span to the 60s due to an epidemic increase in the cardiovascular disease which is a main cause of morbidity and mortality. We cannot underestimate the progress in understanding the major cardiovascular risk factors which include cigarette smoking, dietary, and sedentary lifestyle risks. Despite their clinical significance, these modifiable risk factors are still the major contributors to cardiovascular disease. It is, therefore, important to understand the specific molecular mechanisms behind their pathological effects to develop new therapies to improve the treatment of cardiovascular disease. In recent years, our group and others have made a progress in understanding how these risk factors can promote endothelial dysfunction, smooth muscle dysregulation, vascular inflammation, hypertension, lung, and heart diseases. These factors, despite differences in their nature, lead to stereotypical alterations in vascular metabolism and function. Interestingly, cigarette smoking has a tremendous impact on a very distant site from the initial epithelial exposure, namely circulation and vascular cells mediated by a variety of stable cigarette smoke components which promote vascular oxidative stress and alter vascular metabolism and function. Similarly, dietary and sedentary lifestyle risks facilitate vascular cell metabolic reprogramming promoting vascular oxidative stress and dysfunction. Mitochondria are critical in cellular metabolism, and in this work, we discuss a new concept that mitochondria are a common pathobiological target for these risk factors, and mitochondria-targeted treatments may have a therapeutic effect in the patients with cardiovascular disease.

In recent years, an interesting shift in our understanding of chronic heart failure (CHF) pathophysiology may be observed. Beyond the traditional concepts of hemodynamic failure and neuroendocrine activation, it is increasingly appreciated that CHF is a much more complex and truly systemic disease including the peripheral organs and whole body regulatory processes as well. Novel concepts such as the systemic inflammatory immune activation and the skeletal muscle hypothesis have emerged.1 These concepts recognize the significant contribution of peripheral changes to symptomatic status, disease progression, and outcome in CHF. Article see p 185 A further novel facet in heart failure pathophysiology has emerged recently because impaired regulation of systemic metabolic balance is increasingly in the focus of clinical research. The emerging picture suggests a complex but characteristic pattern of metabolic pathways that are imbalanced, attenuated, or abnormally activated. Hormonal imbalances have been previously observed as common features in CHF, such as insulin resistance2 and growth hormone resistance3 that contribute to both morbidity and mortality of patients. The metabolic interaction of neuroendocrine activation and immune activation such as from cytokines and oxygen radical accumulation add to the complexity of these interrelated processes. In general, the findings repeat, again, the classical concept of short-term beneficial adaptive responses on acute injury or disease may eventually turn into harmful maladaptive signals on prolonged and chronic activation. The overall clinical effects that may be observed from impaired energy metabolic efficacy contribute to impaired exercise capacity, muscle fatigue, and early exhaustion—key symptoms in heart …

Exercise-mediated autophagy in cardiovascular diseases.

Nitric oxide (NO) is an endogenous vasodilator, which was described initially as endothelium-derived relaxing factor (EDRF) by Dr. Robert F. Furchgott. In 1978, he performed an experiment in his laboratory in New York that would lead to his realization that the presence of the endothelium is essential for the vasodilatory effect of acethylcholine. Twenty years after this key experiment, the Nobel prize was awarded to Dr. Furchgott (among others) for the discovery of EDRF. In Endothelium, Nitric Oxide, and Atherosclerosis: From Basic Mechanism to Clinical Implications, which was divided into 4 sections, the first chapter of the first section starts with a review of the discovery, biological roles, and regulation of endothelial NO by Dr. Furchgott himself. This chapter might be a valuable historical reference for anyone interested in this field. Endothelium, Nitric Oxide, and Atherosclerosis: From Basic Mechanism to Clinical Implications is a multiauthored exploration of endothelial cell function, NO, and atherosclerosis, focusing on physiology, biology, histology, and …

Basic science: Pathophysiology: the CardioRenal Metabolic Syndrome

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and age is by far the greatest risk factor for developing CVD. Vascular dysfunction, including endothelial dysfunction and arterial stiffening, is responsible for much of the increase in CVD risk with aging. A key mechanism involved in vascular dysfunction with aging is oxidative stress, which reduces the bioavailability of nitric oxide (NO) and induces adverse changes to the extracellular matrix of the arterial wall (e.g., elastin fragmentation/degradation, collagen deposition) and an increase in advanced glycation end products, which form crosslinks in arterial wall structural proteins. Although vascular dysfunction and CVD are most prevalent in older adults, several conditions can "accelerate" these events at any age. One such factor is chemotherapy with anthracyclines, such as doxorubicin (DOXO), to combat common forms of cancer. Children, adolescents and young adults treated with these chemotherapeutic agents demonstrate impaired vascular function and an increased risk of future CVD development compared with healthy age-matched controls. Anthracycline treatment also worsens vascular dysfunction in mid-life (50-64 years of age) and older (65 and older) adults such that endothelial dysfunction and arterial stiffness are greater compared to age-matched controls. Collectively, these observations indicate that use of anthracycline chemotherapeutic agents induce a vascular aging-like phenotype and that the latter contributes to premature CVD in cancer survivors exposed to these agents. Here, we review the existing literature supporting these ideas, discuss potential mechanisms as well as interventions that may protect arteries from these adverse effects, identify research gaps and make recommendations for future research.

Oxidative stress, lysosomal damage and dysfunctional autophagy in molluscan hepatopancreas (digestive gland) induced by chemical contaminants

Chronic activation of cells of the immune system including T cells and systemic inflammation are well known risk factors for cardiovascular disease (CVD). Many human pathological conditions including viral infections, autoimmune diseases and aging are recognized drivers of increased risk of CVD. Among viral infections, Cytomegalovirus (CMV) infection is a contributing risk element to the existing traditional risk factors of atherogenesis; Influenza infection is correlated with ncreased&#13;\nthe risk of cardiovascular events leading to deaths and HIV infection is an independent predictor of cardiovascular risk. The pandemic of SARS-COV2 infection showed that the severe presentation of the disease manifests with vascular damage and cardiovascular events. Autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic disease are also associated with cardiovascular disease. Lastly, in adults over 65 years, the accumulation of age-related phenotypic and functional alterations in immune cells parallels with a decline of the cardiovascular system with an increased incidence of cardiovascular disease.&#13;\nThe mechanisms behind are not well defined, and while the role of innate immune cells has been established, the involvement of T cells in promoting vascular pathology and cardiovascular disease has emerged more recently (1). Chronic systemic inflammation and increased circulating levels of cytokines and chemokines can indeed contribute to vascular damage by promoting endothelial cell activation and oxidative stress thus linking to the increased risk of CVD (2, 3). Activation of endothelial cells promotes recruitment of circulating immune cells including T cells that will be activated and differentiate into distinct effector cells contributing to the pathology of the disease (4–6). Endothelial cells in this context have also been proposed to act as “semiprofessional” antigen presenting cells (APC) presenting antigens and providing several costimulatory signals to T cells leading to T cell activation especially at sites defined as endothelium-dependent microvascular reactivity sites by Laser Doppler Flowmetry Assessment (7). A milestone in the understanding the role of T cells in promoting vascular inflammation has been reached with the characterization of the immune cell infiltrate in human atherosclerotic plaque by scRNA-seq technology which defined the main subsets of T cells in atherosclerosis (8). This data paved the way for further investigations about the role of T cells as a putative mechanistic link in pathologies associated with an increased risk of CVD. The proposed mechanisms by which T cells contribute to the pathology of the disease include dysregulated T helper and CD8 T cell function, expansion of terminally differentiated cytotoxic effectors CD4+ CD28- T cells and impaired Tregs function. This Research Topic has the aim to provide an overview of the latest advances in the study of the role of T cell activation and endothelial inflammation in cardiovascular risk and disease in the context of infection, autoimmunity and aging. The Research Topic highlights the emerging common and distinctive features of the putative immune mechanistic links between the pathophysiological conditions and the associated cardiovascular disease. The Research Topic comprises 11 articles, original research articles, 5 review and one systematic review and was divided into 3 sections.&#13;\n1. Endothelial inflammation and T cell activation in CVD associated with infection.&#13;\n2. T cell mechanisms involved in CVD associated with autoimmune diseases.&#13;\n3. The immunology of cardiovascular disease during aging.