Study of endothelial dysfunction and vascular inflammation in sleep apnea, obesity and aged humans

Obstructive sleep apnea [OSA] has been associated with cardiovascular complications. The overnight repetitive hypoxia represents a form of oxidative stress in the vasculature which may activate the oxidant-sensitive, proinflammatory transcription factor nuclear factor kjB [NF-kjB], affecting endothelial function and atherosclerosis. We investigated whether the endothelial alterations attributed to OSA rather than to other confounding factors. Also, the production of inflammatory cytokine nuclear factor-kappa beta [NFKbeta] was investigated as the molecular mechanism involved in vascular endothelial dysfunction with OSA. Sixty subjects underwent attended nocturnal polysomnography were grouped by apnea hypopnea index: control [AHI<5/h] and OSA cases [AHI>5/h] the cases were further classified according to age and BMI into subgroup IIA: OSA, non-obese, middle age [35-52 y], subgroup IIB: OSA, non-obese, older age group [55-68 y], subgroup IIIA: OSA, obese, middle age group [35-52 y] and subgroup IIIB: OSA, obese, older age group [55-68 y]. A morning venous blood sample was obtained. Neutrophils were isolated, and NF-kjB activity was determined. Plasma sVCAM-1 was assayed by enzyme-linked immunosorbent assay and flow-mediated dilation [FMD] was performed. NF-jB activation and plasma level of sVCAM-1 were significantly increased in OSA patients as compared to the control group and there was no significant difference between the obese and non-obese cases also no significant difference between the middle and old age cases. The degree of NF-kjB activation was positively correlated with indices of apnea severity[r = 0.938; p< 0.001]. FMD was significantly decreased in OSA patients as compared to the control group. These findings suggested that OSA is an independent risk factor for cardiovascular morbidity also that OSA leads to NF-kjB activation, which may constitute an important pathway linking OSA with systemic inflammation and cardiovascular disease

Effect of estrogen and N-acetyl cystein on bone remodeling and bone cytokine osteoprotegrin in ovarectomized rats

Osteoporosis is one of the most common metabolic bone diseases which is characterized by loss of bone mass and predominantly affects menopausal women due to the loss of estrogen. Although the link between estrogen deficiency and bone loss is well established, the mechanisms through which estrogen deficiency stimulates bone resorption and impairs bone formation remain controversial. Estrogen deficiency may lead to osteoporosis by decreasing the production of osteoprotegrin [OPG], one of the important local regulators of bone turnover or by down regulating antioxidant pathways. We investigated the impact of estrogen deficiency [induced by ovariectomy] on bone cytokine osteoprotegerin and the process of bone remodeling. Also, we compared between the effect of estrogen replacement therapy and thiol antioxidant [NAC] supplementation in the protection against bone loss produced by estrogen deficiency. This study was carried out on fourty female Wistar rats, and divided into two main groups: normal control rats [n=10] and ovariectomized rats [n=30]. The control group was sham operated and received a weekly subcutaneous injection of a vehicle [100 micro L sesame oil]. The ovarectomized group was subjected to ovariectomy and was further subdivided into 3 subgroups; a non-treated group, 17-beta estradiol injected group and N- acetyl cystein [NAC] injected group. At the end of the experimental period, blood samples were collected from all experimental rats for measuring: serum alkaline phosphatase, serum osteocalcin and serum estradiol. Urine samples were also collected for measuring: urine hydroxyproline and urinary calcium excretion. After the rats were sacrificed, one femur from each rat was weighted and homogenized for the estimation of OPG content. In ovariectomized group there was a significant decrease in the serum estradiol level and a significant increase in markers of bone resorption [urinary hydroxyproline and urinary calcium excretion] with a significant but insufficient increase in the markers of bone formation [serum alkaline phosphatase as well as serum osteocalcin] which cause a state of negative remodeling balance. Moreover, there was a significant decrease in bone OPG level as compared to the normal control group. All these effects were reversed in the 17-beta estradiol treated ovariectomized group. In addition, the markers of bone resorption and formation, as well as the OPG level were corrected after administration of NAC in ovariectomized rats. Estrogen deficiency can lead to osteoporosis through reduction of OPG level and increasing in the reactive oxygen species [ROS]. 17-beta estradiol administration leads to increased concentrations of OPG, which inhibits osteoclastogenesis. Also administration of NAC prevents the occurrence of high bone turnover in ovariectomized rats. This effect was suggested to be due to either increase the levels of SOD and GPx which are known to be decreased in ovariectomized rats or through the increased level of OPG by unknown signaling mechanism. Thus it is suggested that NAC can be used in the prevention and treatment of osteoporosis in postmenopausal women either alone or in combination with small doses of estrogen