Diabetes associated with hypertension exacerbated oxidative stress–mediated inflammation, apoptosis and autophagy leading to erectile dysfunction in rats

Abstract

Background: Diabetes or hypertension contributes to erectile dysfunction (ED). We hypothesized that excess reactive oxygen species (ROS) production evoked by diabetes combined with hypertension may further suppress endothelial nitric oxide (NO) expression/activity and promote oxidative stress in the ED penis. Methods: Twenty-four adult male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were divided into four groups: normal WKY, diabetic WKY, normal SHR and diabetic SHR. Intraperitoneal streptozotocin (65 mg/kg) was applied to induce type I diabetes. After 4-week diabetes and/or hypertension induction, we determined the intra-cavernous pressure (ICP) using electrical stimulation of cavernous nerves, intra-cavernosum NO amount using an electrochemical NO probe, and blood ROS using an ultrasensitive chemiluminescence-amplified analyzer. Western blot analysis and immunohistochemistry were used to explore the pathophysiologic mechanisms of inflammation, apoptosis and autophagy in the penis. A novel NO donor, CysaCysd Lu-5 (CCL5, (RCH2CH2S)(R’R”CHCH2S)Fe(NO)2, 1-4 µg), was intravenously administered to these ED rats for evaluating their ICP responses. Results: In the baseline status, the lucigenin- and luminol-amplified blood ROS were significantly enhanced in the diabetic SHR rats vs normal WKY rats. Significantly decreased ICP, eNOS expression and NO amount were found in the normal SHR, diabetic WKY, and diabetic SHR vs normal WKY rats. Intravenous NO donor L-Arginine markedly increased ICP and NO amount, whereas eNOS inhibitor, Nω-Nitro-L-Arginine methyl ester hydrochloride depressed ICP in all four groups. Diabetes and/or hypertension alone increased fibrosis, proinflammatory NF-kB/ICAM-1 expression, mast cell numbers, CD68 expression and infiltration, Caspase 3-mediated apoptosis, Beclin-1/LC3-II–mediated autophagy and mild Nrf-2/HO-1 expression and depressed eNOS expression in the ED penis. The novel NO donor, CCL5, was more efficient than L-arginine to improve diabetes and/or hypertension–induced ED by the significant increase of ICP. Conclusion: Diabetes combined with hypertension synergistically exacerbated ED through enhanced oxidative stress, inflammation, apoptosis and autophagy and depressed eNOS activity and NO production.

Association between Pre-Pregnancy Overweightness/Obesity and Pregnancy Outcomes in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

“…Xue et al further provided a theoretical basis of abnormal endometrium in PCOS women to explain the subfertility of women with PCOS, including anovulation-induced endometrial hyperplasia, hyper-androgenic inhibition of the growth, differentiation and decidualization of the endometrium, IR related disruption of glucose metabolism in the endometrial with subsequent impairment of endometrial receptivity, progesterone resistance of the endometrium and chronic inflammatory change producing a vicious circle that disrupts the physiological endocrine and metabolic microenvironment of the endometrial and affects the receptivity of the endometrium [ 52 ]. Furthermore, obesity is associated with impaired ovarian function, poor oocyte quality and decreased reproductive performance by elevated proinflammatory cytokines, such as interleukin 6 (IL-6) and TNFα as well as oxidative stress [ 53 , 54 ].…”

Negative air ions through the action of antioxidation, anti-inflammation, anti-apoptosis and angiogenesis ameliorate lipopolysaccharide induced acute lung injury and promote diabetic wound healing in rat

“…In this study, we used immunoblotting techniques to measure autophagy-related Beclin-1 and LC3-II, apoptosis-related caspase 3 and poly-(ADP-ribose)-polymerase (PARP) signaling pathway in the lung tissue. The methods have been well established and described previously in our laboratory [ 22 ]. In brief, twenty μg of proteins were used in 10% polyacrylamide gels with electronphoretically transferred to nitrocellulose membranes (Amersham Biosciences, Buckingham, England, UK).…”

“…We assessed the degree of apoptosis by evaluating the expression of caspase 3 and PARP and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay (DNA Fragmentation Kit; BioVision, Milpitas, California, USA) and autophagy by Beclin-1 (Cell Signaling Technology, Inc.) and LC3-II (Cell Signaling Technology, Inc.) staining in the rat lungs. The determined techniques have been followed as reported previously [ 22 ]. In brief, tissue sections from 10% formalin fixation and paraffin embedding were deparaffinized, rehydrated, and stained with H&E or immunohistochemically.…”

The crosstalk among autophagy, apoptosis, and pyroptosis in cardiovascular disease

“…Some intracellular components in autophagy, such as misfolded/aggregated proteins and damaged organelles, are encapsulated by autophagosomes and then delivered to lysosomes or vacuoles for degradation ( 4 ). Current evidence suggests that most CVDs are related to the activation or inhibition of autophagy ( 5 – 11 ). Apoptosis is an activity and PCD mediated by gene regulation, which can lead to morphological and biochemical changes, including cell shrinkage, plasma membrane blebbing, chromosome pyknosis, nuclear fragmentation, and DNA banding, and ultimately phagocytose cells by phagosomes ( 12 ).…”