Role of peroxynitrite in the pathogenesis of cardiovascular complications of diabetes Pa ́ l Pacher and Csaba Szabo ́

National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, 5625 Fishers Lane MSC 9413, Bethesda, Maryland 20852, USA.
Current Opinion in Pharmacology (Impact Factor: 4.6). 05/2006; 6(2):136-41. DOI: 10.1016/j.coph.2006.01.001
Source: PubMed


Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, lead to increased polyol pathway flux, activation of protein kinase C and accelerated non-enzymatic formation of advanced glycation end products. Many of these pathways become activated in response to the production of superoxide anion. Superoxide can interact with nitric oxide, forming the potent cytotoxin peroxynitrite. Peroxynitrite attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, eventually leading to cardiovascular dysfunction via multiple mechanisms. This review focuses on emerging evidence suggesting that peroxynitrite plays a key role in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic retinopathy, neuropathy and nephropathy.

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    • "Metalloporphyrins as peroxynitrite decomposition scavengers have been shown to be effective in a variety of disease models [61], [62], [63], [64], [65], and are promising candidates for clinical trials to prevent oxidative tissue injury and inflammatory response syndrome, especially given the apparently relative broad window of opportunity for their use. Although FeTMPyP and MnTBAP afforded protection in our model, it warrants further investigation for use as therapeutic potential. "
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    ABSTRACT: Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP), water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1) also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.
    PLoS ONE 01/2014; 9(1):e86057. DOI:10.1371/journal.pone.0086057 · 3.23 Impact Factor
    • "ONOO• is a strong oxidizing and nitrating agent, which is involved in the development of a variety of pathological conditions including diabetes, cardiovascular, and neurodegenerative disorders. It plays a key role in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic retinopathy, neuropathy, and nephropathy.[1] An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of NO• have long been proposed to be the common cause of the endothelial dysfunction, resulting from diabetes mellitus.[2] "
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    ABSTRACT: Evidences of oxidative and/or nitrosative stress in type 2 diabetes mellitus were demonstrated in experimental and human studies. This study is aimed to assess the serum peroxynitrite and oxidized lipoproteins in patients with type 2 diabetes mellitus presented with clinical and laboratory evidences of peripheral neuropathy. Eighty four patients with type 2 diabetes mellitus (51 of them had neuropathy) and 31 apparent healthy subjects were studied in the unit of neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq. Neuropathy total symptom score (NTSS), neuropathy impairment score in the lower leg (NIS-LL), and nerve conduction velocity of sensory (ulnar and sural) and motor (ulnar and common peroneal) nerves were used to assess the neuropathy. Fasting venous blood was obtained from each participant for the determination of serum glucose and oxidized lipoproteins. The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components), sural, and common peroneal nerves in diabetic neuropathy compared to diabetics without neuropathy and healthy subjects. Significant high level of serum peroxynitrite was found in diabetic patients with or without neuropathy compared with non-diabetics. The changes in serum-oxidized lipoproteins in patients with diabetics with or without neuropathy were non-significantly differed from healthy subjects. Neither nitrosative stress nor oxidative stress indices correlated with the variables that are related to the neuropathy. It concludes that evidence of nitrosative and to less extent the oxidative stress is associated with neuropathy in type 2 diabetes mellitus and their indices not correlated with variables related to neuropathy.
    Journal of Neurosciences in Rural Practice 03/2012; 3(1):41-4. DOI:10.4103/0976-3147.91932
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    • "Possible mechanisms of ONOO reaction pathways conferring to the proteins (hemoglobin, myoglobin, cytochrome c) and, especially, their scavenging role have been discussed (Pietraforte et al. 2003). Peroxynitrite as a potent cytotoxin plays a key role in the pathogenesis of cardiovascular dysfunction leading to progression of diabetic retinopathy, neuropathy, and nephropathy by attacking various biomolecules in vascular endothelium, vascular smooth muscle, and myocardium (Pacher and Szabó 2006). "
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    ABSTRACT: Current understanding on the role of peroxynitrite in etiology and pathogenesis of some human diseases, such as cardio-vascular diseases, stroke, cancer, inflammation, neurodegenerative disorders, diabetes mellitus and diabetic complications has recently led to intensive investigation of peroxynitrite involvement in physiology and pathophysiology. Mechanism of cytotoxic effects of peroxynitrite involve its reactions with lipids, DNA/RNA, proteins, and polysaccharides, thus triggering cellular responses ranging from subtle changes of cell functioning to severe oxidative damage of the affected macromolecules leading to necrosis or apoptosis. The present work is aimed at providing a brief overview of i) peroxynitrite biosynthesis and reaction pathways in vivo, ii) its synthetic preparation in vitro, and iii) to reveal its potential damaging role in vivo, on actions studied via monitoring in vitro hyaluronan degradation. The complex biochemical behavior of peroxynitrite is determined by a number of variables, such as chemistry of the reaction itself, depending mostly on the involvement of conformational structures of different energy states, concentration of the species involved, content of reactive intermediates and trace transition metal ions, contribution of carbon dioxide, presence of trace organics, and by the reaction kinetics. Recently, in vitro studies of oxidative cleavage of hyaluronan have, in fact, been the subject of growing interest. Here we also describe our experimental set-up for studying peroxynitrite-mediated degradation of hyaluronan, a system, which may be suitable for testing prospective pharmacological substances.
    General Physiology and Biophysics 09/2011; 30(3):223-38. DOI:10.4149/gpb_2011_03_223 · 1.17 Impact Factor
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