The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional monocarboxypeptidase responsible ...for generating Ang-(1-7) from Ang II. ACE2 is important in the vascular system where it is found in arterial and venous endothelial cells and arterial smooth muscle cells in many vascular beds. Among the best characterized functions of ACE2 is its role in regulating vascular tone. ACE2 through its effector peptide Ang-(1-7) and receptor Mas1 induces vasodilation and attenuates Ang II-induced vasoconstriction. In endothelial cells activation of the ACE2/Ang-(1-7)/Mas1 axis increases production of the vasodilator's nitric oxide and prostacyclin's and in vascular smooth muscle cells it inhibits pro-contractile and pro-inflammatory signaling. Endothelial ACE2 is cleaved by proteases, shed into the circulation and measured as soluble ACE2. Plasma ACE2 activity is increased in cardiovascular disease and may have prognostic significance in disease severity. In addition to its enzymatic function, ACE2 is the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV) and SARS-Cov-2, which cause SARS and coronavirus disease-19 (COVID-19) respectively. ACE-2 is thus a double-edged sword: it promotes cardiovascular health while also facilitating the devastations caused by coronaviruses. COVID-19 is associated with cardiovascular disease as a risk factor and as a complication. Mechanisms linking COVID-19 and cardiovascular disease are unclear, but vascular ACE2 may be important. This review focuses on the vascular biology and (patho)physiology of ACE2 in cardiovascular health and disease and briefly discusses the role of vascular ACE2 as a potential mediator of vascular injury in COVID-19.
Abstract Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With ageing the vasculature undergoes structural and functional changes characterised by ...endothelial dysfunction, wall thickening, reduced distensibility and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix remodeling, processes that are associated with aging and amplified by hypertension. Some recently characterised molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases (MMPs), activation of TGFβ1/SMAD signaling, upregulation of galectin-3 and activation of pro-inflammatory and pro-fibrotic signaling pathways. These events can be induced by vasoactive agents, such as angiotensin II (Ang II), endothelin-1 (ET-1) and aldosterone, that are increased in the vasculature during aging and hypertension. Complex interplay between the ‘aging process’ and pro-hypertensive factors results in accelerated vascular remodelling and fibrosis, and increased arterial stiffness, typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of ‘early’ or ‘premature’ vascular aging is now often used to describe hypertension-associated vascular disease. Here, we review the vascular phenotype in ageing and hypertension focusing on arterial stiffness and vascular remodeling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and extracellular matrix reorganisation.
A link between oxidative stress and hypertension has been firmly established in multiple animal models of hypertension but remains elusive in humans. While initial studies focused on inactivation of ...nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly. In this review, we summarize recent advances in delineating the primary and secondary sources of reactive oxygen species (nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, endoplasmic reticulum, and mitochondria), the posttranslational oxidative modifications they induce on protein targets important for redox signaling, their interplay with endogenous antioxidant systems, and the role of inflammasome activation and endoplasmic reticular stress in the development of hypertension. We highlight how oxidative stress in different organ systems contributes to hypertension, describe new animal models that have clarified the importance of specific proteins, and discuss clinical studies that shed light on how these processes and pathways are altered in human hypertension. Finally, we focus on the promise of redox proteomics and systems biology to help us fully understand the relationship between ROS and hypertension and their potential for designing and evaluating novel antihypertensive therapies.
Microparticles: biomarkers and beyond Burger, Dylan; Schock, Sarah; Thompson, Charlie S ...
Clinical science (1979),
04/2013, Letnik:
124, Številka:
7
Journal Article
Recenzirano
Membrane microparticles are submicron fragments of membrane shed into extracellular space from cells under conditions of stress/injury. They may be distinguished from other classes of extracellular ...vesicles (i.e. exosomes) on the basis of size, content and mechanism of formation. Microparticles are found in plasma and other biological fluids from healthy individuals and their levels are altered in various diseases, including diabetes, chronic kidney disease, pre-eclampsia and hypertension among others. Accordingly, they have been considered biomarkers of vascular injury and pro-thrombotic or pro-inflammatory conditions. In addition to this, emerging evidence suggests that microparticles are not simply a consequence of disease, but that they themselves may contribute to pathological processes. Thus microparticles appear to serve as both markers and mediators of pathology. The present review examines the evidence for microparticles as both biomarkers of, and contributors to, the progression of disease. Approaches for the detection of microparticles are summarized and novel concepts relating to the formation of microparticles and their biological effects are examined.
Abstract Ageing is associated with functional, structural and mechanical changes in arteries that closely resemble the vascular alterations in hypertension. Characteristic features of large and small ...arteries that occur with ageing and during the development of hypertension include endothelial dysfunction, vascular remodelling, inflammation, calcification and increased stiffness. Arterial changes in young hypertensive patients mimic those in old normotensive individuals. Hypertension accelerates and augments age-related vascular remodelling and dysfunction, and ageing may impact on the severity of vascular damage in hypertension, indicating close interactions between biological ageing and blood pressure elevation. Molecular and cellular mechanisms underlying vascular alterations in ageing and hypertension are common and include aberrant signal transduction, oxidative stress and activation of pro-inflammatory and pro-fibrotic transcription factors. Strategies to suppress age-associated vascular changes could ameliorate vascular damage associated with hypertension. An overview on the vascular biology of ageing and hypertension is presented and novel molecular mechanisms contributing to these processes are discussed. The complex interaction between biological ageing and blood pressure elevation on the vasculature is highlighted. This article is part of a Special Issue entitled: CV Ageing.
: The healthy endothelium prevents platelet aggregation and leucocyte adhesion, controls permeability to plasma components and maintains vascular integrity. Damage to the endothelium promotes ...endothelial dysfunction characterized by: altered endothelium‐mediated vasodilation, increased vascular reactivity, platelet aggregation, thrombus formation, increased permeability, leucocyte adhesion and monocyte migration. Molecular processes contributing to these phenomena include increased expression of adhesion molecules, synthesis of pro‐inflammatory and pro‐thrombotic factors and increased endothelin‐1 secretion. Decreased nitric oxide bioavailability and increased generation of reactive oxygen species (ROS) are among the major molecular changes associated with endothelial dysfunction. A critical source of endothelial ROS is a family of non‐phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, including the prototypic Nox2‐based NADPH oxidases, Nox1, Nox4 and Nox5. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase and uncoupled nitric oxide synthase (NOS). Cross‐talk between ROS‐generating enzymes, such as mitochondrial oxidases and Noxs, is increasingly implicated in cellular ROS production. The present review discusses the importance of endothelial ROS in health and disease and focuses on the major ROS‐generating systems in the endothelium, namely uncoupled endothelial nitric oxide synthase and NADPH oxidases.
Abstract
Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological ...mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration (Ca2+i), promoting actin-myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase, protein Kinase C and mitogen-activated protein kinase signalling, reactive oxygen species, and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and non-coding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell Ca2+i not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signalling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here, we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension.
The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with ...androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function nitric oxide (NO) release, Ca
mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.
TRPM7, Magnesium, and Signaling Zou, Zhi-Guo; Rios, Francisco J; Montezano, Augusto C ...
International journal of molecular sciences,
04/2019, Letnik:
20, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme that possesses an ion channel permeable to the divalent cations Mg
, Ca
, and Zn
, and an ...α-kinase that phosphorylates downstream substrates. TRPM7 and its homologue TRPM6 have been implicated in a variety of cellular functions and is critically associated with intracellular signaling, including receptor tyrosine kinase (RTK)-mediated pathways. Emerging evidence indicates that growth factors, such as EGF and VEGF, signal through their RTKs, which regulate activity of TRPM6 and TRPM7. TRPM6 is primarily an epithelial-associated channel, while TRPM7 is more ubiquitous. In this review we focus on TRPM7 and its association with growth factors, RTKs, and downstream kinase signaling. We also highlight how interplay between TRPM7, Mg
and signaling kinases influences cell function in physiological and pathological conditions, such as cancer and preeclampsia.
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