Acute myocardial infarction (MI) and its consequences are the most common and lethal heart syndromes worldwide and represent a significant health problem. Following MI, apoptosis has been generally seen as the major contributor of the cardiomyocyte fate and of the resultant myocardial remodeling. However, in recent years, it has been discovered that, following MI, cardiomyocytes could activate autophagy in an attempt to protect themselves against ischemic stress and to preserve cardiac function. Although initially seen as two completely separate responses, recent works have highlighted the intertwined crosstalk between apoptosis and autophagy. Numerous researches have tried to unveil the mechanisms and the molecular players involved in this phenomenon and have identified in high-mobility group box 1 (HMGB1), a highly conserved non-histone nuclear protein with important roles in the heart, one of the major regulator. Thus, the aim of this mini review is to discuss how HMGB1 regulates these two responses in ischemic heart diseases. Indeed, a detailed understanding of the crosstalk between apoptosis and autophagy in these pathologies and how HMGB1 regulates them would be of tremendous help in developing novel therapeutic approaches aimed to promote cardiomyocyte survival and to diminish tissue injury following MI.
Eleonora Foglio, Laura Pellegrini, Antonia Germani, Matteo Antonio Russo, and Federica Limana
Carlo Dal Lin, Francesco Tona, and Elena Osto
The heart and the immune system are highly integrated systems cross-talking through cytokines, hormones and neurotransmitters. Their balance can be altered by numerous physical or psychological stressors leading to the onset of inflammation, endothelial dysfunction and tissue damage. Here, we review the main players and mechanisms involved in the field. A new research paradigm, which considers also novel contributors, like endothelial cells, is needed to better understand the pathophysiology of immune-mediated cardiovascular disorders and beyond.
Ornella Colpani and Gaia Spinetti
During organism aging, the process of cellular senescence is triggered by critical stressors such as DNA damage, oncogenes, oxidative stress, and telomere erosion, and vascular cells are not exempted. Senescent cells stop proliferating but remain metabolically active producing pro-inflammatory signals in the environment collectively named senescence-associated secretory phenotype (SASP) that contribute to the amplification of the response to the neighbor and distant cells. Although the shift toward senescence is protective against tumors and needed during wound healing, the accumulation of senescent cells during aging due to an impairment of the immune system deputed to their clearance, can predispose to diseases of the cardiovascular system such as atherosclerosis. In this short review, we describe the main features of senescence of endothelial and smooth muscle cells and focus on the role non-coding RNAs of the microRNAs class in controlling this process. Finally, we discuss the potential of new strategies based on senescence removal in counteracting vascular disease burden.
Raafat Mohamed, Reearna Janke, Wanru Guo, Yingnan Cao, Ying Zhou, Wenhua Zheng, Hossein Babaahmadi-Rezaei, Suowen Xu, Danielle Kamato, and Peter J Little
The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.
Stephen P Gray, Ajay M Shah, and Ioannis Smyrnias
The heart relies on complex mechanisms that provide adequate myocardial oxygen supply in order to maintain its contractile function. At the cellular level, oxygen undergoes one electron reduction to superoxide through the action of different types of oxidases (e.g. xanthine oxidases, uncoupled nitric oxide synthases, NADPH oxidases or NOX). Locally generated oxygen-derived reactive species (ROS) are involved in various signaling pathways including cardiac adaptation to different types of physiological and pathophysiological stresses (e.g. hypoxia or overload). The specific effects of ROS and their regulation by oxidases are dependent on the amount of ROS generated and their specific subcellular localization. The NOX family of NADPH oxidases is a main source of ROS in the heart. Seven distinct Nox isoforms (NOX1–NOX5 and DUOX1 and 2) have been identified, of which NOX1, 2, 4 and 5 have been characterized in the cardiovascular system. For the purposes of this review, we will focus on the effects of NADPH oxidase 4 (NOX4) in the heart.
Xuechong Hong and Wenduo Gu
Vascular remodeling is a complex and dynamic pathological process engaging many different cell types that reside within the vasculature. Mesenchymal stromal/stem cells (MSCs) refer to a heterogeneous cell population with the plasticity to differentiate toward multiple mesodermal lineages. Various types of MSC have been identified within the vascular wall that actively contribute to the vascular remodeling process such as atherosclerosis. With the advances of genetic mouse models, recent findings demonstrated the crucial roles of MSCs in the progression of vascular diseases. This review aims to provide an overview on the current knowledge of the characteristics and behavior of vascular resident MSCs under quiescence and remodeling conditions, which may lead to the development of novel therapeutic approaches for cardiovascular diseases.
Sandra Neumann, Elena G Milano, Chiara Bucciarelli-Ducci, and Giovanni Biglino
This mini review provides a concise overview of imaging techniques that are currently used to image the atheroscletoric plaque in the carotid artery in vivo. The main techniques include ultrasound imaging, X-ray imaging, magnetic resonance imaging and positron emission tomography imaging. Each technique has advantages and limitations and may be chosen depending on the availability, cost and clinical justification for its use. Common to all the imaging techniques presented here is the need for a skilled imaging professional to allow for high reliability and repeatability. While ultrasound-based imaging currently is regarded as a first line technique in clinical practice, the use of other techniques such as computed tomography angiography or magnetic resonance angiography need to be considered in the presence of significant stenosis with or without symptoms. Advancements in these two modalities, as well as in positron emission tomography imaging, are increasingly moving toward a better understanding of the risk-stratification and pre-interventional monitoring of patients at risk of plaque rupture as well as early identification of plaque development and better understanding of plaque composition (e.g. metabolic imaging).
David Mellis and Andrea Caporali
MicroRNAs (miRNAs) are small non-coding RNAs that orchestrate genetic networks by modulating gene expression. Given their importance in vascular development, homeostasis and diseases, along with the technical feasibility in deploying their function in vivo, the so-called ‘vascular miRNAs’ have become key targets for therapeutic intervention. Herein, we have summarised the state-of-the-art on vascular miRNAs and we have discussed the role miRNA biogenesis and the extracellular vesicles (EVs) miRNA transport in vascular biology.
Timothy D Le Cras and Elisa Boscolo
The phosphoinositide 3-kinase (PI3K) pathway is a major mediator of growth factor signaling, cell proliferation and metabolism. Somatic gain-of-function mutations in PIK3CA, the catalytic subunit of PI3K, have recently been discovered in a number of vascular anomalies. The timing and origin of these mutations remain unclear although they are believed to occur during embryogenesis. The cellular origin of these lesions likely involves endothelial cells or an early endothelial cell lineage. This review will cover the diseases and syndromes associated with PIK3CA mutations and discuss the cellular origin, pathways and mechanisms. Activating PIK3CA ‘hot spot’ mutations have long been associated with a multitude of cancers allowing the development of targeted pharmacological inhibitors that are FDA-approved or in clinical trials. Current and future therapeutic approaches for PIK3CA-related vascular anomalies are discussed.
Ambra Cappelletto and Serena Zacchigna
Cardiac ischemia is the leading cause of morbidity and mortality in a worldwide epidemic. The progressive understanding of the mechanisms driving new blood vessel formation has led to numerous attempts to revascularize the ischemic heart in animal models and in humans. Here, we provide an overview of the current state of the art and discuss the major obstacles that have so far limited the clinical success of cardiac revascularization.