TNF-α, Erectile Dysfunction, and NADPH Oxidase-Mediated ROS Generation in Corpus Cavernosum in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Abstract

Introduction Patients with diabetes-associated erectile dysfunction (ED) are characterized by an increase in circulating tumor necrosis factor-alpha (TNF-α). However, no study has indicated whether and how TNF-α plays a role in the pathogenesis of ED associated with diabetes. Aim We examined the effects and potential mechanism of infliximab (INF), a chimeric monoclonal antibody to TNF-α, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats. Methods Four groups of male rats were used: age-matched normal controls; diabetic rats induced by a high-fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, intraperitoneal [i.p.]); nondiabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, serum TNF-α measurement, penile ROS detection, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) in the penis. Main Outcome Measures The effect of INF on HFD/STZ-induced diabetic ED and NADPH oxidase-mediated ROS generation was studied in diabetic corpus cavernosum. Results Untreated diabetic rats displayed significantly decreased erectile parameters, and increased plasma TNF-α levels, penile ROS production, p47phox and gp91phox expression compared with nondiabetic controls. INF neutralized TNF-α and significantly reduced ED in diabetic rats, in which marked decreases in p47phox and gp91phox expression and ROS generation in corpus cavernosum were noted. The ratio of phospho-eNOS to eNOS and expression of nNOS in the penis were significantly increased in INF-treated vs. untreated diabetic rats. Conclusions Increased TNF-α expression associated with diabetes contributes to ED by promoting NAPDH oxidase-mediated ROS generation in corpus cavernosum. INF protects against diabetic ED by neutralizing TNF-α.

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit

“…TNFR1 has a ubiquitous distribution (endothelial and smooth muscle cells), whereas TNFR2 expression is mostly confined to cell of hematopoietic origin (Ryffel and Mihatsch, 1993). TNFR1 selectively mediates the majority of the toxic and pro-atherogenic effects of TNFa (Zhang et al, 2010) and is also expressed by the penis (present study and Carneiro et al, 2010;Long et al, 2012). However, the relative abundance of TNFa and TNFR1 mRNA in rabbit penis was rather low and similar to other urogenital tissues.…”

“…Infliximab did not normalize T level, but significantly increased eNOS expression and normalized Ach responsiveness in penis. Similar effects of infliximab on penile function have already been observed in a rat model of HFD/STZ type 2 diabetes (Long et al, 2012). Conversely, infliximab treatment did not affect either the relaxant response to SNP (a NO donor, which bypasses endogenous NO formation), or the expression of genes downstream NO signaling (GCa3, CGb3, PKG1).…”

ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro

“…Thus, the The high blood glucose in diabetes mellitus puts the body in a state of high oxidative stress, with damage to the corpora cavernosa nerves and endothelial cells, as well as inactivation of neuronal and endothelial nitric oxide synthase, leading to decreased production of nitric oxide and diabetes mellitus erectile dysfunction [18,19] . In the rat model of diabetic ED caused by streptozotocin, the products of oxidative stress, such as malonaldehyde, were accumulated, while antioxidant substances (eg, SOD and glutathione) were decreased, resulting in increased ROS levels in the corpus cavernosum [32,33] . Recent investigations have demonstrated that ROS affect the self-renewal and differentiation of bone marrow mesenchymal stem cells, accelerate aging in stem cells and endothelial progenitor cells, increase apoptosis and reduce the self-healing of damaged blood vessels [34,35] .…”

Safety and Potential Therapeutic Effect of Two Intracavernous Autologous Bone Marrow Derived Mesenchymal Stem Cells injections in Diabetic Patients with Erectile Dysfunction: An Open Label Phase I Clinical Trial

“…It has been proposed that hyperglycemia in diabetics leads to smooth muscle dysfunction by the oxidation of low density lipoprotein and increased production of free-oxygen radical species, in addition to mitochondrial fragmentation and cellular apoptosis which leads to endothelial dysfunction resulting in decreased the amount of Nitrous Oxide (NO) production in cavernous tissue [15,16].…”