Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis.

RATIONALE: Atherosclerotic lesions develop in regions of disturbed flow, whereas laminar flow protects from atherogenesis; however, the mechanisms involved are not completely elucidated. Integrins are mechanosensors of shear stress in endothelial cells, and integrin-linked kinase (ILK) is important for blood vessel integrity and cardiovascular development. OBJECTIVES: To explore the role of ILK in vascular function by studying conditionally ILK-deficient (cKO) mice and human atherosclerotic arteries. RESULTS: ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofolate reductase expression, and increased eNOS-dependent generation of superoxide accompanied by extensive vascular protein nitration. ILK reexpression prevented eNOS uncoupling in cKO cells, whereas superoxide formation was unaffected by ILK depletion in eNOS-KO cells, indicating eNOS as a primary source of superoxide anion. eNOS and ILK coimmunoprecipitated in aortic lysates from control animals, and eNOS-ILK-shock protein 90 interaction was detected in human normal mammary arteries but was absent from human atherosclerotic carotid arteries. eNOS-ILK interaction in endothelial cells was prevented by geldanamycin, suggesting heat shock protein 90 as a binding partner. CONCLUSIONS: Our results identify ILK as a regulatory partner of eNOS in vivo that prevents eNOS uncoupling, and suggest ILK as a therapeutic target for prevention of endothelial dysfunction related to shear stress-induced vascular diseases.

Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism.

RATIONALE: Concomitant deep vein thrombosis (DVT) in patients with acute pulmonary embolism (PE) has an uncertain prognostic significance. OBJECTIVES: In a cohort of patients with PE, this study compared the risk of death in those with and those without concomitant DVT. METHODS: We conducted a prospective cohort study of outpatients diagnosed with a first episode of acute symptomatic PE. Patients underwent bilateral lower extremity venous compression ultrasonography to assess for concomitant DVT. MEASUREMENTS AND MAIN RESULTS: The primary study outcome, all-cause mortality, and the secondary outcome of PE-specific mortality were assessed during the 3 months of follow-up after PE diagnosis. Multivariate Cox proportional hazards regression was done to adjust for significant covariates. Of 707 patients diagnosed with PE, 51.2% (362 of 707) had concomitant DVT and 10.9% (77 of 707) died during follow-up. Patients with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.24 to 3.38; P = 0.005) and PE-specific mortality (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.04) compared with those without concomitant DVT. In an external validation cohort of 4,476 patients with acute PE enrolled in the international multicenter RIETE Registry, concomitant DVT remained a significant predictor of all-cause (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001) and PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01). CONCLUSIONS: In patients with a first episode of acute symptomatic PE, the presence of concomitant DVT is an independent predictor of death in the ensuing 3 months after diagnosis. Assessment of the thrombotic burden should assist with risk stratification of patients with acute PE.

Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN.

Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.

Changes in Soluble TWEAK Concentrations, but Not Those in Amyloid-ß(1-40), Are Associated with a Decrease in Carotid Intima-Media Thickness after Bariatric Surgery in Obese Women.

BACKGROUND/AIM: Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and amyloid-ß(1-40) (Aß40) emerged as markers of cardiovascular risk because of their actions in the endothelium and their role in atherosclerotic progression. The aim of this study was to analyze the association of these two factors with the decrease in carotid intima-media thickness (cIMT) after bariatric surgery in obese women. METHODS: We studied 60 severely obese women, of whom 20 were submitted to laparoscopic Roux-en-Y gastric bypass (RYGB), 20 to sleeve gastrectomy (SG), and 20 to lifestyle modification therapy. Circulating sTWEAK, Aß40, high-sensitivity C-reactive protein, plasminogen activator inhibitor type 1, insulin resistance (HOMA-IR), and cIMT were measured at baseline and after 1 year of follow-up. RESULTS: sTWEAK increased similarly after both surgical procedures, whereas the increase observed after lifestyle intervention did not reach statistical significance. Aß40 showed no differences between groups of women, nor did it change during follow-up. The decrease in cIMT at 12 months correlated with the decrease in body mass index (BMI) (r = 0.45; p < 0.001) and fasting insulin (r = 0.30; p = 0.038), and also with the increase in sTWEAK (r = -0.43; p = 0.002). Multivariate linear regression showed that only the changes in BMI (ß = 0.389; p = 0.005) and sTWEAK (ß = -0.358; p = 0.009) were associated with the decrease in cIMT (R2 = 0.313; F = 9.348; p < 0.001). CONCLUSIONS: One year after bariatric surgery, RYGB and SG induced a similar increase in circulating sTWEAK that occurred in parallel to the decrease observed in cIMT.

Circulating adiponectin increases in obese women after sleeve gastrectomy or gastric bypass driving beneficial metabolic changes but with no relationship with carotid intima-media thickness.

BACKGROUND & AIMS: Obesity surgery induces beneficial effects in metabolic and cardiovascular parameters. Adiponectin increase might be associated with some of these changes. However, direct comparison between different surgical techniques has not been extensively performed. METHODS: We studied 20 obese women submitted to laparoscopic Roux en Y gastric bypass (RYGB) and 20 to sleeve gastrectomy (SG). Twenty control women matched for age and baseline metabolic profiles were also included. Both patients and controls were followed up for one year after surgery or conventional treatment with diet and exercise, respectively. Serum adiponectin was measured at baseline, 6 months and 1 year after, as well as lipid profiles, sex hormone binding globulin (SHBG), fasting glucose and insulin. Carotid intima-media thickness was measured by ultrasonography at baseline and after 1 year. RESULTS: Circulating adiponectin increased after obesity surgery (more markedly following RYGB than after SG), whereas no changes were observed in the controls (Wilks' λ = 0.659, P < 0.001 for the interaction, P < 0.001 for RYGB vs. controls, P = 0.016 for SG vs. controls, P = 0.040 for RYGB vs. SG). The percentage increment in adiponectin correlated positively with changes in SHBG (r = 0.404, P = 0.002) and negatively with changes in weight (r = -0.531, P < 0.001), waist circumference (r = -0.426, P = 0.001), fasting glucose (r = -0.356, P = 0.006), and insulin (r = -0.496, P < 0.001). No correlation was found with carotid intima-media thickness (r = -0.055, P = 0.679). CONCLUSIONS: RYGB induces a higher increase in adiponectin than SG, which parallels SHBG, the reduction of fasting insulin and insulin resistance. On the other hand, no association was found with carotid intima-media, lipid profiles or blood pressure.

Improvement in cardiovascular risk in women after bariatric surgery as measured by carotid intima-media thickness: comparison of sleeve gastrectomy versus gastric bypass.

BACKGROUND: Bariatric surgery may diminish cardiovascular risk (CVR) and its associated mortality. However, studies that compare these effects with different techniques are scarce. OBJECTIVE: To evaluate the changes in CVR as estimated by carotid intima-media thickness (IMT) after obesity surgery in women with high CVR as defined by the presence of metabolic syndrome. SETTING: Academic hospital. METHODS: We studied 40 severely obese women, of whom 20 received laparoscopic Roux en Y gastric bypass (RYGB) and 20 received sleeve gastrectomy (SG). Twenty control women matched for age and cardiovascular risk were also included. Patients and controls were evaluated at baseline and 1 year after surgery or conventional treatment with diet and exercise, respectively. Only 18 of the 20 women in the control group were available for analysis after 1 year. None of the women who had bariatric surgery was lost to follow-up. RESULTS: Mean carotid IMT decreased 1 year after surgery irrespective of the surgical technique used, whereas no changes were observed in the control women who had conventional therapy (Wilks´ λ = .802, P = .002 for the interaction, P = .011 for RYGB versus controls, P = .002 for SG versus controls, P = .349 for RYGB versus SG). CONCLUSION: Both RYGB and SG decrease CVR as measured by carotid IMT in obese women.