Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(3), P. 924 - 967

Published: June 4, 2021

The endothelium, a cellular monolayer lining the blood vessel wall, plays critical role in maintaining multiorgan health and homeostasis. Endothelial functions include dynamic maintenance of vascular tone, angiogenesis, hemostasis, provision an antioxidant, anti-inflammatory, antithrombotic interface. Dysfunction endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion hyperpermeability, endothelial cell senescence. Recent studies have implicated altered metabolism endothelial-to-mesenchymal transition as new features dysfunction. dysfunction is regarded hallmark many diverse human panvascular diseases, including atherosclerosis, hypertension, diabetes. has also been severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors interleukin 1β monoclonal antibodies, counter part their clinical benefits. regulation by noncoding RNAs provided novel insights into these newly described regulators dysfunction, thus yielding potential therapeutic approaches. Altogether, better understanding versatile (dys)functions cells will not only deepen our comprehension diseases but accelerate effective drug discovery. In this review, we provide timely overview multiple layers function, describe consequences mechanisms identify pathways targeted therapies.

Significance Statement

was initially considered be semipermeable biomechanical barrier gatekeeper health. recent decades, deepened biological led its recognition ubiquitous tissue regulating behavior, innate immunity, cell-cell interactions, wall. cardiovascular, metabolic, emerging infectious diseases. Pharmacotherapies targeting for treatment cardiovascular other

Language: Английский

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Cellular senescence: all roads lead to mitochondria

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(5), P. 1186 - 1202

Published: Jan. 20, 2022

Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction several age-related conditions. This has spurred academic community industry to identify new therapeutic interventions targeting this process. Mitochondrial often-unappreciated hallmark cellular senescence which plays important roles not only growth but also development SASP resistance cell-death. Here, we review supports role for mitochondria describe underlying mechanisms. Finally, propose detailed road map mitochondrial biology will be crucial guide future senotherapies.

Language: Английский

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SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis

Circulation Research, Journal Year: 2020, Volume and Issue: 128(4), P. 474 - 491

Published: Dec. 23, 2020

Rationale: Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved response signaling, inflammation, metabolism; however, its role regulating VSMC unclear. Objective: We examined expression human VSMCs, the role, regulation, downstream pathways activated by SIRT6, how regulates atherogenesis. Methods Results: protein, but not mRNA, was markedly reduced VSMCs mouse atherosclerotic plaques, derived from plaques or undergoing replicative palmitate-induced versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus HSC70-interacting protein) promoted stability, palmitate p38- c-Jun N-terminal kinase-dependent manner. bound to telomeres, while inhibition using shRNA deacetylase-inactive mutant (SIRT6 H133Y ) shortened lifespan induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation 53BP1 (p53 binding protein 1) binding, indicative damage. In contrast, overexpression preserved integrity, delayed cellular inflammatory cytokine changes metabolism senescence. , proliferation prevented senescence-associated metabolic changes. ApoE −/− (apolipoprotein E) mice were generated that overexpress only. SM22α-hSIRT6/ApoE had atherosclerosis, markers inflammation compared littermate controls, SM22α-hSIRT6 /ApoE showed increased instability. Conclusions: positively regulated CHIP. maintenance inhibits atherogenesis, all dependent on activity. Our data show endogenous an important unrecognized inhibitor atherosclerosis.

Language: Английский

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Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes

Cytokine & Growth Factor Reviews, Journal Year: 2020, Volume and Issue: 53, P. 33 - 37

Published: May 4, 2020

Language: Английский

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Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: New insights into the mechanisms and therapeutic potentials

Pharmacological Research, Journal Year: 2020, Volume and Issue: 156, P. 104771 - 104771

Published: March 28, 2020

Language: Английский

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SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 15, 2021

Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial can promote chronic inflammation disease processes like thrombosis, atherosclerosis, lung injury. In cells, mitochondria regulate these pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that initiate exacerbate senescence, a state promotes dysfunction. Oxidative also activate feedback loops perpetuate dysfunction, overproduction, inflammation. this review, we provide an overview of phenotypes mediated by - such inflammation, senescence well how states may be initiated cells. We propose activates mtROS-mediated cause long-term changes host status function, promoting cardiovascular injury after recovery from COVID-19. Finally, discuss the implications proposed on vascular health potential treatments to address conditions.

Language: Английский

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The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: May 12, 2021

In recent decades, the mechanism underlying bone metabolic disorders based on energy metabolism has been heavily researched. Bone resorption by osteoclasts plays an important role in occurrence and development of osteoporosis. However, osteoclast disorder that interferes with homeostasis not determined. is a process consumes large amounts adenosine triphosphate (ATP) produced glycolysis oxidative phosphorylation. addition to glucose, fatty acids amino can also be used as substrates produce through this review, we summarize analyze energy-based phenotypic changes, epigenetic regulation, coupling systemic during progression At same time, propose hypothesis, compensatory recovery (involving balance between survival functional activation), which may provide new approach for treatment

Language: Английский

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Periodontal microorganisms and Alzheimer disease – A causative relationship?

Periodontology 2000, Journal Year: 2022, Volume and Issue: 89(1), P. 59 - 82

Published: March 4, 2022

Abstract In the initiation or exacerbation of Alzheimer disease, dissemination oral microorganisms into brain tissue low‐level systemic inflammation have been speculated to play a role. However, impact microorganisms, such as Porphyromonas gingivalis , on pathogenesis disease and potential causative relationship is still unclear. The present review has critically reviewed literature by examining following aspects: (a) microbiome immune response in elderly population, (b) human studies association between periodontal gut (c) animal vitro (d) preventive therapeutic approaches. Factors contributing microbial dysbiosis seem be aging, local inflammation, diseases, wearing dentures, living nursing homes no access adequate hygiene measures. was detectable post‐mortem samples. Microbiome analyses saliva samples biofilms showed decreased diversity different composition compared cognitively healthy subjects. Many in‐vitro underline P induce disease‐related alterations. models, recurring applications its components increased pro‐inflammatory mediators β‐amyloid deteriorated animals' cognitive performance. Since periodontitis result disturbed homoeostasis, an effect therapy host related parameters may suggested should elucidated further clinical trials.

Language: Английский

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Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance

Angiogenesis, Journal Year: 2022, Volume and Issue: 25(3), P. 307 - 329

Published: March 18, 2022

Language: Английский

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Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: Sept. 30, 2023

Abstract During aging and after traumatic injuries, cartilage bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, proinflammatory cytokines. This detrimental environment triggers cellular stress subsequent dysfunction, which not only contributes the development of associated diseases, that is, osteoporosis osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated reduce overall tissue damage, possess diverse defense mechanisms. However, antioxidative capacities limited thus ROS accumulation can lead aberrant cell fate decisions, have adverse effects on homeostasis. In this narrative review, we address oxidative as a major driver processes in bone, senescence, misdirected differentiation, death, mitochondrial impaired mitophagy by illustrating consequences homeostasis regeneration. Moreover, elaborate mechanisms, with particular focus response mitophagy, briefly discuss respective therapeutic strategies improve protection.

Language: Английский

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