Redox Control of Vascular Function

Straub, Adam C.

doi:10.1161/atvbaha.117.309945

Cited by 27 publications

(12 citation statements)

References 102 publications

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“…Such forces might come into play in the setting of HIV-linked CVD. The Nrf2 pathway also has a protective role in atherosclerosis, consistent with its suppression of NADP(P)H oxidase (NOX)4, which can injure endothelium 93. The orally bioavailable Nrf2 activator S-adenosyl-L-methionine (SAMe), the main endogenous methyl donor,94 could prevent and treat ethanol-associated and lipid-associated hepatic fibrosis and asthma-associated pulmonary fibrosis in mice 95 96.…”

Section: Introductionmentioning

confidence: 98%

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

2018

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HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015–March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-β1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions.

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Section: Introductionmentioning

confidence: 98%

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

2018

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“…Although reactive oxygen species (ROS) were initially presumed to cause cell damage, they are now recognized as important molecules that regulate many cell signaling and biological processes, such as induction of defense genes, activation of transcription factors, phosphorylation of kinases, and mobilization of ions in transport systems (reviewed in Droge, 2002; Touyz and Briones, 2011; Brown and Griendling, 2015). In the cardiovascular system, ROS generation is important to maintain endothelial and vascular smooth muscle cells (VSMCs) function, including vascular tone control, inflammation-related responses, cell growth and proliferation, modulation of extracellular matrix production, apoptosis and angiogenesis (Siti et al, 2015; reviewed in Galley and Straub, 2017). Alterations of the balance between cellular ROS production and the capacity to rapidly detoxify reactive intermediates play an important role in the development of risk factors for cardiovascular diseases (reviewed in Harrison et al, 2003 and Touyz et al, 2018).…”

Section: Overview Of Reactive Oxygen Species and Cardiovascular Functionmentioning

confidence: 99%

Nrf2 as a Potential Mediator of Cardiovascular Risk in Metabolic Diseases

et al. 2019

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Free radicals act as secondary messengers, modulating a number of important biological processes, including gene expression, ion mobilization in transport systems, protein interactions and enzymatic functions, cell growth, cell cycle, redox homeostasis, among others. In the cardiovascular system, the physiological generation of free radicals ensures the integrity and function of cardiomyocytes, endothelial cells, and adjacent smooth muscle cells. In physiological conditions, there is a balance between free radicals generation and the activity of enzymatic and non-enzymatic antioxidant systems. Redox imbalance, caused by increased free radical’s production and/or reduced antioxidant defense, plays an important role in the development of cardiovascular diseases, contributing to cardiac hypertrophy and heart failure, endothelial dysfunction, hypertrophy and hypercontractility of vascular smooth muscle. Excessive production of oxidizing agents in detriment of antioxidant defenses in the cardiovascular system has been described in obesity, diabetes mellitus, hypertension, and atherosclerosis. The transcription factor Nrf2 (nuclear factor erythroid 2–related factor 2), a major regulator of antioxidant and cellular protective genes, is primarily activated in response to oxidative stress. Under physiological conditions, Nrf2 is constitutively expressed in the cytoplasm of cells and is usually associated with Keap-1, a repressor protein. This association maintains low levels of free Nrf2. Stressors, such as free radicals, favor the translocation of Nrf2 to the cell nucleus. The accumulation of nuclear Nrf2 allows the binding of this protein to the antioxidant response element of genes that code antioxidant proteins. Although little information on the role of Nrf2 in the cardiovascular system is available, growing evidence indicates that decreased Nrf2 activity contributes to oxidative stress, favoring the pathophysiology of cardiovascular disorders found in obesity, diabetes mellitus, and atherosclerosis. The present mini-review will provide a comprehensive overview of the role of Nrf2 as a contributing factor to cardiovascular risk in metabolic diseases.

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“…EC function is all but static and effective as a summation and processing of multiple stimuli by individual cells, often within close proximity along the same vessel segment. Signalling affecting EC behaviour often involves generating and responding to reactive oxygen species (ROS) , which can be generated by the EC themselves or by neighbouring cells, as a result of metabolic shifts, injury or damage, or an immune response . It has been shown that the ROS‐associated antioxidant machinery expressed in EC is unique to vessel type and location within the vascular tree and organ of origin , suggesting that tolerance to oxidative stress is tissue‐specific, and some EC are more responsive/susceptible to oxidative damage than others.…”

Section: Regulation and Regulators Of Ec Function In Different Tissuesmentioning

confidence: 99%

Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

Reiterer

Branco

2019

The FEBS Journal

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The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self‐regulate and to respond to organ demand and environmental stimuli. Endothelial cells from different organs display considerable variation, but it is currently unclear to what extent functional properties of organ‐specific endothelial cells are intrinsic, acquired and/or reprogrammable. Vascular function is a fundamental pillar of homeostasis, and dysfunction results in systemic consequences for the organism. Additionally, vascular failure can occur downstream of organ disease or environmental stress, often driving an exacerbation of symptoms and pathologies originally independent of the local circulation. The understanding of the molecular mechanisms underlying endothelial physiology and metabolism holds the promise to inform and improve diagnosis, prognosis and treatment options for a myriad of conditions as unrelated as cancer, neurodegeneration or pulmonary hypertension, and likely everything in between, if we consider that also treatments for such conditions are primarily distributed via the bloodstream. However, studying endothelial function has its challenges: the origin, isolation, culture conditions and preconditioning stimuli make this an extremely variable cell type to study and difficult to source. Animal models exist but are neither trivial to generate, nor necessarily adequately translatable to human disease. In this article, we aim to illustrate the breadth of microvascular functions in different environments, highlighting current and pioneering studies that have advanced our insight into the importance of the integrity of this tissue, as well as the limitations posed by its heterogeneity and plasticity.

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Redox Control of Vascular Function

Cited by 27 publications

References 102 publications

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies

Nrf2 as a Potential Mediator of Cardiovascular Risk in Metabolic Diseases

Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

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