Contribution of oxidative stress to endothelial dysfunction in hereditary hemorrhagic telangiectasia

Frontiers in Genetics
Mirjana Jerkic, Michelle Letarte

Abstract

Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS) play a crucial role in hereditary hemorrhagic telangiectasia (HHT) disease, a vascular dysplasia affecting 1 in 5,000-8,000 people. Mutations in endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. ENG and ACVRL1 interact with endothelial nitric oxide synthase (eNOS) and regulate its activation. Mice heterozygous for these genes (Eng (+/-) and Acvrl1 (+/-)) show reduced ENG or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of ROS rather than nitric oxide (NO•), leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng (+/-) and Acvrl1 (+/-) mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng (+/-) and Acvrl1 (+/-) mice also develop with age signs of pulmonary arterial hypertension attributable to eNOS-derived ROS, which was preventable by antiox...Continue Reading

References

Apr 14, 1994·The New England Journal of Medicine·UNKNOWN Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
Nov 24, 1999·The Journal of Clinical Investigation·A BourdeauM Letarte
Jun 29, 2000·The American Journal of Clinical Nutrition·C M LoriaP K Whelton
Feb 18, 2003·Human Molecular Genetics·Sudha SrinivasanDouglas A Marchuk
Jan 22, 2004·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mirjana JerkicJ M López-Novoa
May 1, 2004·Cleveland Clinic Journal of Medicine·Bibi I Hasnain, Arshag D Mooradian
May 10, 2005·Journal of Medical Genetics·S A Abdalla, M Letarte
Jul 5, 2005·Journal of Medical Genetics·S G ColeC L Shovlin
Jun 6, 2006·Nature Medicine·Shivalingappa VenkateshaS Ananth Karumanchi
Sep 14, 2006·American Journal of Medical Genetics. Part a·Pinar Bayrak-ToydemirRong Mao
Sep 20, 2007·Journal of Cardiovascular Pharmacology·An L Moens, David A Kass
Feb 16, 2008·European Journal of Cardiovascular Prevention and Rehabilitation : Official Journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology·Zheng Ye, Honglin Song
Oct 13, 2009·American Journal of Physiology. Lung Cellular and Molecular Physiology·J BelikM Letarte
Jan 9, 2010·American Journal of Respiratory and Critical Care Medicine·Barbara GirerdMarc Humbert
Feb 16, 2010·Pharmacology & Therapeutics·Christopher S Wilcox
Apr 29, 2010·Current Hypertension Reports·Antje R Weseler, Aalt Bast
Sep 24, 2010·British Journal of Pharmacology·S WindK Wingler
Oct 27, 2010·European Heart Journal·Thomas MünzelStefano Taddei
Dec 17, 2010·World Journal of Cardiology·Jui-Chih ChangChin-San Liu
Jan 5, 2011·Antioxidants & Redox Signaling·Michael E Widlansky, David D Gutterman
May 7, 2011·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jamie McDonaldReed E Pyeritz
Jul 13, 2011·The Journal of Cell Biology·Toren Finkel
Jul 23, 2011·Free Radical Biology & Medicine·Sergey Dikalov
Aug 24, 2011·Cardiovascular Research·Mirjana JerkicMichelle Letarte
Mar 13, 2012·Vascular Pharmacology·Agata SchrammTomasz J Guzik
Mar 27, 2012·The Canadian Journal of Cardiology·Augusto C Montezano, Rhian M Touyz
Jan 16, 2013·Oxidative Medicine and Cellular Longevity·Mirjana JerkicMichelle Letarte
Nov 5, 2013·Current Pharmaceutical Design·Huige Li, Ulrich Forstermann
Jun 21, 2014·Arteriosclerosis, Thrombosis, and Vascular Biology·Scott A BarmanDavid J R Fulton
Jul 14, 2014·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Hyo-Bum KwakJohn M Lawler
Jul 30, 2014·Trends in Endocrinology and Metabolism : TEM·Grant R Drummond, Christopher G Sobey

❮ Previous
Next ❯

Citations

Aug 2, 2017·Journal of Functional Biomaterials·Hidenobu OhtaNobuo Yaegashi
Aug 11, 2017·Expert Opinion on Therapeutic Targets·Lidia Ruiz-LlorenteCarmelo Bernabeu
Jan 30, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Konstantinos GkatzisFranck Lebrin
Jun 18, 2016·Zeitschrift für Rheumatologie·A KucukM Kayrak
Nov 11, 2020·Journal of Clinical Medicine·Carmelo BernabeuMichelle Letarte
Dec 22, 2020·Journal of Cellular Physiology·S Krithika, S Sumi

❮ Previous
Next ❯

Related Concepts

Related Feeds

Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory genetically determined disease of the skin marked by increased ability to form reagin (IgE), with increased susceptibility to allergic rhinitis and asthma, and hereditary disposition to a lowered threshold for pruritus. Discover the latest research on atopic dermatitis here.

Cardiovascular Disease Pathophysiology

Cardiovascular disease involves several different processes that contribute to the pathological mechanism, including hyperglycemia, inflammation, atherosclerosis, hypertension and more. Vasculature stability plays a critical role in the development of the disease. Discover the latest research on cardiovascular disease pathophysiology here.