Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling

Published on May 19, 2020in Frontiers in Pharmacology4.225
· DOI :10.3389/FPHAR.2020.00727
Anida Velagic2
Estimated H-index: 2
(Monash University),
Chengxue Qin17
Estimated H-index: 17
(Monash University)
+ 3 AuthorsBarbara K Kemp-Harper29
Estimated H-index: 29
(Monash University)
Sources
Abstract
Diabetes is associated with an increased mortality risk due to cardiovascular complications. Hyperglycemia-induced oxidative stress underlies these complications, leading to an impairment in endogenous nitric oxide (NO.) generation, together with reductions in NO. bioavailability and NO. responsiveness in the vasculature, platelets and myocardium. The latter impairment of responsiveness to NO., termed NO. resistance, compromises the ability of traditional NO.-based therapeutics to improve hemodynamic status during diabetes-associated cardiovascular emergencies, such as acute myocardial infarction. Whilst a number of agents can ameliorate (e.g. angiotensin converting enzyme [ACE] inhibitors, perhexiline, statins and insulin) or circumvent (e.g. nitrite and sGC activators) NO. resistance, nitroxyl (HNO) donors offer a novel opportunity to circumvent NO resistance in diabetes. With a suite of vasoprotective properties and an ability to enhance cardiac inotropic and lusitropic responses, coupled with preserved efficacy in the setting of oxidative stress, HNO donors have intact therapeutic potential in the face of diminished NO. signaling. This review explores the major mechanisms by which hyperglycemia-induced oxidative stress drives NO. resistance, and the therapeutic potential of HNO donors to circumvent this to treat cardiovascular complications in type 2 diabetes mellitus.
📖 Papers frequently viewed together
30 Citations
44 Citations
References202
Newest
#1Alan S. Go (KP: Kaiser Permanente)H-Index: 124
#2Andrew P. Ambrosy (UCSF: University of California, San Francisco)H-Index: 18
Last. Patient Risks StudyH-Index: 1
view all 11 authors...
ABSTRACT The association between statins and diabetes mellitus (DM) remains controversial. The Kaiser Permanente CHAMP Study identified adults without DM who had CV risk factors and no prior lipid lowering therapy (LLT) between 2008 and 2010. The CV risk factors included known atherosclerotic CV disease (ASCVD), elevated low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL, or an LDL-C between 70-189 mg/dL and an estimated 10-year ASCVD risk ≥7.5%. Incident DM was defined as ≥2 abnormal tests ...
3 CitationsSource
#1Chengxue Qin (Monash University)H-Index: 17
#2Jarryd Anthonisz (Monash University)H-Index: 2
Last. Rebecca H. Ritchie (Monash University)H-Index: 39
view all 12 authors...
Aim: Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NO•), known as NO• resistance, occurs in many cardiovascular disease states, prominently in diabetes and especiall...
9 CitationsSource
#1Rajaa Almourani (MU: University of Missouri)H-Index: 2
#2Bhavana Chinnakotla (MU: University of Missouri)H-Index: 2
Last. James R. Sowers (MU: University of Missouri)H-Index: 115
view all 5 authors...
Purpose of Review Cardiovascular disease (CVD) is the leading cause of mortality in people with diabetes. Our aim was to review the pathophysiology of CVD in diabetes, review related landmark trials, and discuss the cardiovascular benefit of glucose-lowering agents. We have also discussed the role of controversial anti-platelet therapy.
13 CitationsSource
#1Pouya Saeedi (International Diabetes Federation)H-Index: 12
#2Inga Petersohn (International Diabetes Federation)H-Index: 2
Last. Dominic Bright (Swansea University)H-Index: 2
view all 13 authors...
Abstract Aims To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045. Methods A total of 255 high-quality data sources, published between 1990 and 2018 and representing 138 countries were identified. For countries without high quality in-country data, estimates were extrapolated from similar countries matched by economy, ethnicity, geography and language. Diabetes prevalence (including previously undiagnosed diabetes) in adults aged 20 to 79 years was estim...
1,654 CitationsSource
#1Piotr Ruszkowski (Medical University of Łódź)H-Index: 1
#2Anna Masajtis-Zagajewska (Medical University of Łódź)H-Index: 8
Last. Michał P Nowicki (Medical University of Łódź)H-Index: 11
view all 3 authors...
Background:The aim of this study was to compare the influence of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on endothelial function and blood pressure in patients with essential hyp...
6 CitationsSource
#1Sinan Subhi Farhan (Alrafidain University College)H-Index: 1
#2Saad Abdulrahmann Hussain (Alrafidain University College)H-Index: 1
Abstract Aim To evaluate the role advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) expression levels as predictors of vascular complications in uncontrolled type 2 diabetes mellitus (T2DM). Methods Cross-sectional study was conducted on T2DM adults of both sexes who attended the outpatient service of Al-Karak Teaching Hospital, Jordan during the period from June 2017 to August 2018. Participants were categorized in two groups according to their glycemic control and the ...
9 CitationsSource
#1G. Michael Felker (Duke University)H-Index: 94
#2Maria Borentain (BMS: Bristol-Myers Squibb)H-Index: 7
Last. John J.V. McMurray (Glas.: University of Glasgow)H-Index: 197
view all 10 authors...
Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post-translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological ...
11 CitationsSource
: Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1...
8 CitationsSource
#1Christin ElgertH-Index: 2
#2Anne RühleH-Index: 2
Last. Sönke BehrendsH-Index: 6
view all 4 authors...
Abstract The soluble guanylyl cyclase (sGC) plays a key role in NO/cGMP signalling and is widely recognised to be important in different disease pathomechanisms. The discovery of sGC agonists provides a new opportunity to stimulate the NO/cGMP pathway. One class of compounds are the heme-independent sGC activators, which are thought to bind to oxidised or heme-free sGC. This enzyme is preferentially formed under disease situations accompanied by oxidative stress. Accordingly, this binding mode o...
5 CitationsSource
#1Yilin Yoshida (MU: University of Missouri)H-Index: 6
#2Suzanne Austin Boren (MU: University of Missouri)H-Index: 28
Last. Eduardo J. Simoes (MU: University of Missouri)H-Index: 32
view all 8 authors...
Purpose of Review To identify a common effect of health information technologies (HIT) on the management of cardiovascular disease (CVD) risk factors among people with type 2 diabetes (T2D) across randomized control trials (RCT).
8 CitationsSource
Cited By5
Newest
#1Guillermo Carrone (Facultad de Ciencias Exactas y Naturales)H-Index: 3
#2Agostina Mazzeo (Facultad de Ciencias Exactas y Naturales)H-Index: 2
Last. Fabio Doctorovich (Facultad de Ciencias Exactas y Naturales)H-Index: 28
view all 8 authors...
Abstract null null We present a novel nitroxyl (HNO) generation method, which avoids the need of using a liquid system or extreme experimental conditions. This method consists of the reaction between a gaseous base and an HNO donor (Piloty’s acid) in the solid phase, allowing the formation of gaseous HNO in a fast and economical way. Detection of HNO was carried out indirectly, measuring the nitrous oxide (N2O) byproduct of HNO dimerization using infrared spectroscopy, and directly, using mass s...
1 CitationsSource
#1Sebastian Suarez (CONICET: National Scientific and Technical Research Council)H-Index: 14
#2Paola Vargas (CONICET: National Scientific and Technical Research Council)H-Index: 5
Last. Fabio Doctorovich (CONICET: National Scientific and Technical Research Council)H-Index: 2
view all 3 authors...
Abstract Azanone (HNO/NO−), also called nitroxyl, is a highly reactive compound whose biological role is still a matter of debate. A key issue that remains to be clarified regarding HNO and its biological activity is that of its endogenous formation. Given the overlap of the molecular targets and reactivity of nitric oxide (NO•) and HNO, its chemical biology was perceived to be similar to that of NO• as a biological signaling agent. However, despite their closely related reactivity, NO• and HNO'...
4 CitationsSource
#1Jasmin Chendi LiH-Index: 1
#2Anida VelagicH-Index: 2
Last. Owen L. Woodman (Monash University)H-Index: 3
view all 8 authors...
Introduction. Endothelial dysfunction is a major risk factor for several of vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one-electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but roles of HNO in diabetes-mellitus associated endothelial dysfunction in the carotid-artery remains unknown. Aim. To assess how diabetes affects roles of endogenous-NO• and-HNO in endothelium-dependent relaxation in rat-isolated car...
1 CitationsSource
#1Hadeel A. Alsufyani (KAU: King Abdulaziz University)H-Index: 2
#2James R. Docherty (RCSI: Royal College of Surgeons in Ireland)H-Index: 42
The ongoing pandemic has stimulated study of the Renin Angiotensin Aldosterone System (RAAS), and how it can be manipulated to treat COVID-19 Studies are examining whether drugs that act on the RAAS system might be useful to treat COVID-19 COVID-19 and the RAAS are closely linked both in infection and in possible post-infection inflammatory cascades We detail the Physiology and Pharmacology of the RAAS including the effects of aldosterone and atrial natriuretic peptide It is appropriate that the...
2 CitationsSource
#1Barbara K Kemp-Harper (Monash University, Clayton campus)H-Index: 29
#2Anida Velagic (Monash University)H-Index: 2
Last. Rebecca H. RitchieH-Index: 39
view all 5 authors...
Reactive oxygen species (ROS) dysregulation is a hallmark of cardiovascular disease, characterised by an imbalance in the synthesis and removal of ROS. ROS such as superoxide (•O2-), hydrogen peroxide (H2O2), hydroxyl (OH•) and peroxynitrite (ONOO-) have a marked impact on cardiovascular function, contributing to the vascular impairment and cardiac dysfunction associated with diseases such as angina, hypertension, diabetes and heart failure. Central to the vascular dysfunction is a reduction in ...
1 CitationsSource