Role of apoptosis and oxidative stress in high glucose-induced endothelial dysfunction in isolated aortic rings

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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Low-Density Lipoprotein-Cholesterol-Induced Endothelial Dysfunction and Oxidative Stress: The Role of Statins

Antioxidants and Redox Signaling ◽

10.1089/ars.2013.5537 ◽

2014 ◽

Vol 20 (8) ◽

pp. 1216-1237 ◽

Cited By ~ 34

Author(s):

Nerea Hermida ◽

Jean-Luc Balligand

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

And Oxidative Stress

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Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8671713 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Adriana Fodor ◽

Brandusa Tiperciuc ◽

Cezar Login ◽

Olga H. Orasan ◽

Andrada L. Lazar ◽

...

Keyword(s):

Oxidative Stress ◽

Respiratory Failure ◽

Endothelial Dysfunction ◽

Clinical Manifestations ◽

Therapeutic Targets ◽

Lung Damage ◽

Wide Range ◽

Underlying Mechanisms ◽

And Oxidative Stress

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

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