Defect In Endothelial Function Research Articles

Prevalence of endothelial dysfunction in acquired immune deficiency syndrome patients and its correlation with degree of immunodeficiency

Background: Number of factors play a role in endothelial dysfunction observed in AIDS patients, which can lead to atherosclerosis along with cardiovascular mortality and morbidity. Human immunodeficiency virus (HIV), the etiologic agent of AIDS causes several vascular disorders characterized by an evident activation and perturbation of endothelial cells. Currently, there is lack of data in the Indian literature regarding study of endothelial dysfunction in HIV patients. The purpose of our research was to study the prevalence of endothelial dysfunction in HIV/AIDS patients.Methods: The study comprises a total number of 60 adult HIV positive patients of both sex (male and female) with confirmed HIV seropositivity. The patients were divided into two groups of 30 each, depending on the degree of immune dysfunction (CD 4 cell counts). Group I- patients with CD 4+T cell count>200/µl and group II-patients with CD 4+T cell count<200/µl. These patients were subjected to detailed clinical examination and markers of endothelial dysfunction-flow mediated vasodilatation (FMD) of brachial artery, S. nitrite and C-reactive protein (CRP) were performed.Results: The defect in endothelial function was most prevalent in patients with more severe immunosuppression. FMD of brachial artery was decreased in patients with CD 4+T cell count < 200/µl (7.07±2.89, p=0.00). S. nitrite was also significantly lower in group II patients (26.43±15.38), and these patients also showed more CRP positivity and higher CRP titres ranging from 1.2 mg/dl to 9.6 mg/dl.Conclusions: The defect in endothelial function was most prevalent in patients with more severe immunosuppression. FMD of brachial artery was decreased in patients with CD 4+T cell count <200/µl (7.07±2.89, p=0.00). S. nitrite was also significantly lower in group II patients (26.43±15.38), and these patients also showed more CRP positivity and higher CRP titres ranging from 1.2 mg/dl to 9.6 mg/dl.

Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.

Objective- Mitochondria are the important yet most underutilized target for cardio-cerebrovascular function integrity and disorders. The Tom (translocases of outer membrane) complex are the critical determinant of mitochondrial homeostasis for making organs acclimate physiological and pathological insults; however, their roles in the vascular system remain unknown. Approach and Results- A combination of studies in the vascular-specific transgenic zebrafish and genetically engineered mice was conducted. Vascular casting and imaging, endothelial angiogenesis, and mitochondrial protein import were performed to dissect potential mechanisms. A loss-of-function genetic screening in zebrafish identified that selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities. Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function. Mechanistically, Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling, which incurred angiogenic impairment that underlies cerebrovascular network malformation. Conclusions- Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium.

ATP-binding cassette transporter G1 protects against endothelial dysfunction induced by high glucose

IntroductionIt is known that hyperglycaemia can contribute to defects in endothelial function, which is the early characteristic of atherosclerosis. ATP-binding cassette transporter G1 (ABCG1), a regulator of reversing cholesterol efflux,...

Is there a vasospasmolytic effect of acupuncture in patients with secondary Raynaud phenomenon?

Raynaud phenomenon (RP) is a vasospastic disorder of the digital arteries. Severe forms are found in patients with connective tissue diseases. Vasospasmolytic therapies are often limited by side effects such as orthostatic hypotension. We investigated therefore the effect of acupuncture in a double blind, placebo-controlled, randomized trial in patients with secondary RP. The study was performed during the winter season by licensed acupuncturists weekly for 8 weeks (points chosen for the verum group: L.I.4, S.J.5, St.36, P.6, Du.20, Ex.28). An improvement was detected in both groups but there was no significant effect on clinical symptoms - based on patient diaries (average number of attacks before and after treatment: verum 1.9 +/- 2.0 vs. 1.4 +/- 1.7 attacks/ day and placebo 2.8 +/- 1.8 vs. 1.9 +/- 1.1; duration of attacks: verum 15 +/- 12 vs. 12 +/- 9 min. and placebo 31 +/- 17 vs. 16 +/- 6; n.s.) or on skin microcirculation, measured by local cold testing. A specific vasospasmolytic effect of acupuncture could not be proven. This may be due to minor morphologic changes of supplying arteries or a severe local defect in endothelial function rather than a neurological disturbance which might be influenced by acupuncture. Much larger studies would be needed to identify the possible small benefit from acupuncture. If long-term relief is not obtained, it is unlikely to be cost-effective.

Mesenteric vascular bed responsiveness in bile duct-ligated rats: roles of opioid and nitric oxide systems

Changes in vascular responsiveness are proposed as the basis for some of the cardiovascular complications in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and evidence of overproduction of nitric oxide (NO). The possible role of NO or opioid system in cholestasis-induced mesenteric vascular bed responsiveness was investigated. Bile duct-ligated and sham-operated rats were treated for 6 days with either normal saline, naltrexone, an opioid antagonist (20 mg/kg/day) or l-NAME ( N(ω)-nitro- l-arginine methyl ester), a nitric oxide synthase inhibitor (3 mg/kg/day). After 7 days, the superior mesenteric artery was cannulated and the mesenteric vascular bed was perfused according to the McGregor method. Baseline perfusion pressure of the mesenteric vascular bed was decreased in bile duct-ligated compared to sham-operated animals. ED 50 of phenylephrine-induced vasoconstriction was increased, but vasoconstriction R max was not different in the vascular bed of bile duct-ligated rats and of sham-operated ones. Acetylcholine-induced vasorelaxation was impaired in bile duct-ligated rats (increased ED 50 and decreased vasorelaxation R max). Sodium nitroprusside-induced vasorelaxation was not different between bile duct-ligated and sham-operated rats, implying that the smooth muscle components of vasorelaxation were intact. Chronic treatment with l-NAME partially restored both the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction response in bile duct-ligated rats. Naltrexone treatment also partially restored the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction in bile duct-ligated rats. There is impaired acetylcholine-induced vasorelaxation in cholestatic rats, probably due to a defect in endothelial function. This study also provided evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced vascular hyporesponsiveness.

Glutathione reverses endothelial damage from peroxynitrite, the byproduct of nitric oxide degradation, in crystalloid cardioplegia.

NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO(-)). ONOO(-) in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO(-) may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO(-) and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia. In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 micromol/L authentic ONOO(-); catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO(-). In 1 group (CP+GSH, n=5), the cardioplegia contained 500 micromol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, n=6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0+/-2.4 versus CP+GSH 10.6+/-1.3 mm Hg/mL) or diastolic chamber stiffness (ss-coefficient: CCP 0.35+/-0.2 versus CP+GSH 0.31+/-0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CP+GSH versus CCP (2.2+/-0.7 versus 5.4+/-1.2, P:<0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CP+GSH than in CCP (118+/-6% versus 92+/-5%, P:<0.05), with a smaller EC(50) value (-7. 10+/-0.05 versus -6.98+/-0.03, respectively, P:<0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CP+GSH than in CCP (98+/-18 versus 234+/-36 neutrophils/mm(2), P:<0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO(-) and GSH, was greater in CP+GSH than in CCP (4.1+/-2.3 versus 0.4+/-0.2 microg/mL, P:<0.05). GSH in crystalloid cardioplegia detoxifies ONOO(-) and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage.

Glutathione Reverses Endothelial Damage From Peroxynitrite, the Byproduct of Nitric Oxide Degradation, in Crystalloid Cardioplegia

Background —NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO − ). ONOO − in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO − may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO − and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia. Methods and Results —In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 μmol/L authentic ONOO − ; catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO − . In 1 group (CP+GSH, n=5), the cardioplegia contained 500 μmol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, n=6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0±2.4 versus CP+GSH 10.6±1.3 mm Hg/mL) or diastolic chamber stiffness (β-coefficient: CCP 0.35±0.2 versus CP+GSH 0.31±0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CP+GSH versus CCP (2.2±0.7 versus 5.4±1.2, P &lt;0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CP+GSH than in CCP (118±6% versus 92±5%, P &lt;0.05), with a smaller EC 50 value (−7.10±0.05 versus −6.98±0.03, respectively, P &lt;0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CP+GSH than in CCP (98±18 versus 234±36 neutrophils/mm 2 , P &lt;0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO − and GSH, was greater in CP+GSH than in CCP (4.1±2.3 versus 0.4±0.2 μg/mL, P &lt;0.05). Conclusions —GSH in crystalloid cardioplegia detoxifies ONOO − and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage.

This Month in the Journal

This Month in the Journal

Southwestern Internal Medicine Conference: Endothelial Dysfunction and Vascular Disease

Vascular endothelial cells, critically situated at the blood-tissue interface, exert important effects on vascular tone and permeability, regulate the coagulation and fibrinolytic systems, mediate translocation of inflammatory cells to the tissue compartment, and modulate proliferation of vascular smooth muscle cells. As the physiology of the endothelium has been defined, defects in endothelial function have been identified in association with human disease, and a syndrome of dysfunctional endothelium has been described. Although it remains debatable whether a coherent syndrome of endothelial dysfunction exists, disordered endothelial biology appears to contribute to the pathophysiology of human vascular disease. Identification of specific molecular mechanisms offers potential targets for novel therapeutic interventions, including genetic modification of endothelial cells in vivo.