Nitroglycerin Attenuates Human Endothelial Progenitor Cell Differentiation, Function, and Survival

Fraccarollo

et al. 2007

ATVB

Key Words: endothelial progenitor cells Ⅲ nitrates Ⅲ nitric oxide Ⅲ reactive oxygen species Ⅲ atherosclerosis Ⅲ free radicals N itrate compounds have been used in the treatment of myocardial ischemia for more than a hundred years. Their common mechanism is the release of nitric oxide (NO), but the majority of nitrates, such as nitroglycerine (NTG) or isosorbide-5-dinitrate (ISDN), additionally stimulate production of reactive oxygen species (ROS). [1][2][3][4][5] This may counteract the beneficial effects of NO on the endothelium. 6 Indeed, NTG treatment was shown to reduce NO bioavailability 1 as a result of increased superoxide anion (O 2 Ϫ ) and peroxynitrite production. 7,8 Clinically, prolonged NTG therapy leads to the development of endothelial dysfunction and nitrate tolerance. 2,9 Therefore, the use of long-acting nitrates with less development of tolerance has become routine in chronic treatment of cardiac ischemia. However, even long-acting nitrates, such as ISDN, may increase ROS production in endothelial cells, smooth muscle cells, and platelets (reviewed by Schwemmer and Bassenge 10 ). In contrast, treatment with pentaerythritol tetranitrate (PETN) was not associated with increased ROS production in patients. 2 PETN treatment did also not stimulate endothelial ROS formation, and displayed antiatherosclerotic effects. 11-13 Indeed, PETN, but not ISDN, prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. 11,14 Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the blood and contribute to the formation of new blood vessels and homeostasis of the vasculature. 15,16 NO is a major regulator of EPC mobilization, differentiation, and function. [17][18][19][20] Although nitrates are potent NO releasing substances, the effects of long-acting nitrates on circulating levels and function of EPCs have not been determined so far. We therefore compared the effects of ISDN and PETN (or its major metabolite pentaerythrityl trinitrate [PETriN]) on EPC number and function in healthy rats and rats after myocardial infarction. Additional in vitro studies were performed with human EPCs to identify potential underlying events leading to the different effects of both nitrates.

Section: Discussionmentioning

confidence: 99%

“…45 Ex vivo NTG exposure increased apoptosis and decreased phenotypic differentiation of EPCs. 45 In the present study, we demonstrate therapy with two different long-acting nitrates to increase levels of circulating EPCs. However, functionally there were strong differences between the tested nitrates.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Organic Nitrates on Endothelial Progenitor Cells Are Determined by Oxidative Stress

Fraccarollo

et al. 2007

ATVB

“…27,28 This represents a potentially important source of "high-output" NO production that may be associated with oxidative stress and the production of reactive NO species that attenuate the mobilization, function, and survival of EPCs. 29,30 Increasing evidence indicates that inflammation has a key role in the pathogenesis of PAH. As in earlier studies, [31][32][33] we found evidence of chronic inflammation with raised plasma levels of the inflammatory mediators TNF-␣, IL-6, and CCL-2.…”

Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

et al. 2008

Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34 + , CD34 + /AC133 + , CD34 + /KDR + , and CD34 + /AC133 + /KDR + progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

“…Among factors involved in reducing the bioavailability of NO, recent work reported by researchers confirm that the development of tolerance to nitrates is associated with increased oxidative stress (Oelze et al, 2010;DiFabio et al, 2006;Muller et al, 2004;Parker, 2004;Gori et al, 2001;Laight et al, 1997Laight et al, , 1998. In addition, a key enzyme involvement of nitroglycerin and nitrates biotransformation, namely the mitochondrial aldehyde dehydrogenase (ALDH 2), is inhibited by reactive oxygen species (ROS) which in addition, can degrade nitric oxide (Wenzel et al, , 2009bDaiber et al, 2004Daiber et al, , 2009bSydow et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

Sarr

Sar²,

Diao³

et al. 2013

J. Clin. Med. Res.

Treatment failure or tolerance, which rapidly leads to a reduced hemodynamic effects and therapeutic efficacy is the major limitation of long-term use of nitrates, including nitroglycerin (NTG) in the treatment of coronary artery disease. These effects are most often associated with oxidative stress. Thus, in this work, we were interested in the prevention of nitrate tolerance by the antioxidant compounds from Hibiscus sabdariffa L. crude extract, a plant from the Senegalese Pharmacopoeia, rich in polyphenols. Thoracic aorta segments without endothelium were taken from rats and incubated in isolated organ chambers. The vessels were then pre-exposed with the H. sabdariffa polyphenolic extract (HSE, 5.10 -2 g/l) or antioxidants such as N-acetyl cysteine (NAC, 10 -3 M) or vitamin C (VIT C, 10 -2 M), taken as reference. After a 30 min treatment, aortic segments were exposed to NTG (50 μM, 1 h) to induce tolerance state before being contracted to adrenaline (10 -8 to 10 -5 M), and then relaxed with NTG (10 -9 to 10 -5 M). Polyphenols from H. sabdariffa potentiated the relaxant response to NTG, whatever the state of vascular tolerance; the HSE partially corrected the in vitro nitrate tolerance. This work suggests interesting therapeutic perspectives by improving the response to treatment with nitrates in coronary patients.