Mitochondria and endothelial function Kluge, Matthew A; Fetterman, Jessica L; Vita, Joseph A
Circulation research,
2013-Apr-12, Letnik:
112, Številka:
8
Journal Article
Recenzirano
Odprti dostop
In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. This article provides ...an overview of key aspects of mitochondrial biology in endothelial cells, including subcellular location, biogenesis, dynamics, autophagy, reactive oxygen species production and signaling, calcium homeostasis, regulated cell death, and heme biosynthesis. In each section, we introduce key concepts and then review studies showing the importance of that mechanism to endothelial control of vasomotor tone, angiogenesis, and/or inflammatory activation. We particularly highlight the small number of clinical and translational studies that have investigated each mechanism in human subjects. Finally, we review interventions that target different aspects of mitochondrial function and their effects on endothelial function. The ultimate goal of such research is the identification of new approaches for therapy. The reviewed studies make it clear that mitochondria are important in endothelial physiology and pathophysiology. A great deal of work will be needed, however, before mitochondria-directed therapies are available for the prevention and treatment of cardiovascular disease.
There is a large unmet need for off-the-shelf biomaterial options to supplant venous autografts in bypass and reconstructive surgical procedures. Existing graft alternatives formed from ...non-degradable synthetic polymers are not capable of maintaining long-term patency and are thus not indicated for <6 mm inner diameter bypass procedures. To fill this void, degradable silk-based biomaterials have been proposed that can maintain their mechanical properties (i.e. compliance) while facilitating slow but progressive biomaterial remodeling and host integration mediated by cellular colonization. The goal of the present study was to enhance the porosity of gel-spun silk tubes, to facilitate faster degradation rates and improve cellularity, and thus improve host integration over time in vivo, while maintaining requisite mechanical functions. Silk solutions with a range of molecular weight distributions and, in turn, viscosities were used to generate tubes of varying porosities. A decrease in solution concentration correlated with an increase in mean pore size and overall porosity through a density-dependent mechanism. Tubes were mechanically analyzed, and these properties were the basis of an analytical model used to correlate tube formulations to structural compliance, which were shown to be similar to the saphenous vein. Tubes were also tested for suture retention to ensure surgical utility despite increased porosity. Tubes were implanted in the abdominal aorta of Sprague-Dawley rats via an end-to-end anastomosis model. Tubes with higher porosities showed early improvements in cell colonization that progressively increased over time; conversely, the dense architecture of less porous grafts (20MB) inhibited cell ingrowth and resulted in minimal biomaterial degradation at the 6-month time point. None of the highly porous tubes (5 MB and 10MB) remained patent at 6 months, likely due remodeling inducing bulk mechanical failure or a compromised blood-material interface.
Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely ...understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species. We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes mellitus.
We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1; P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared with healthy control subjects (n=9). In cultured human aortic endothelial cells exposed to 30 mmol/L glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial reactive oxygen species production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase and cGMP production. Silencing Fis1 or Drp1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, reactive oxygen species production, endothelial nitric oxide synthase activation, and cGMP production. An intracellular reactive oxygen species scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased reactive oxygen species.
These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.
Aorto-atrial fistula is a rare and life-threatening complication of infective endocarditis, classically diagnosed by visualizing a connection between the aorta and atrium with associated continuous ...flow. A patient presented with bioprosthetic and native valve enterococcal endocarditis with multiple complications, including an aorto-atrial fistula that was diagnosed by color M-mode on transesophageal echocardiography. We review the features of aorto-atrial fistula and utilize this case to demonstrate how M-mode can be leveraged to provide improved temporal resolution in the setting of diagnostic uncertainty.
Background: Cranberry juice contains polyphenolic compounds that could improve endothelial function and reduce cardiovascular disease risk.
Objective: The objective was to examine the effects of ...cranberry juice on vascular function in subjects with coronary artery disease.
Design: We completed an acute pilot study with no placebo (n = 15) and a chronic placebo-controlled crossover study (n = 44) that examined the effects of cranberry juice on vascular function in subjects with coronary artery disease.
Results: In the chronic crossover study, subjects with coronary heart disease consumed a research preparation of double-strength cranberry juice (54% juice, 835 mg total polyphenols, and 94 mg anthocyanins) or a matched placebo beverage (480 mL/d) for 4 wk each with a 2-wk rest period between beverages. Beverage order was randomly assigned, and participants refrained from consuming other flavonoid-containing beverages during the study. Vascular function was measured before and after each beverage, with follow-up testing ≥12 h after consumption of the last beverage. Mean (±SD) carotid-femoral pulse wave velocity, a measure of central aortic stiffness, decreased after cranberry juice (8.3 ± 2.3 to 7.8 ± 2.2 m/s) in contrast with an increase after placebo (8.0 ± 2.0 to 8.4 ± 2.8 m/s) (P = 0.003). Brachial artery flow-mediated dilation, digital pulse amplitude tonometry, blood pressure, and carotid-radial pulse wave velocity did not change. In the uncontrolled pilot study, we observed improved brachial artery flow-mediated dilation (7.7 ± 2.9% to 8.7 ± 3.1%, P = 0.01) and digital pulse amplitude tonometry ratio (0.10 ± 0.12 to 0.23 ± 0.16, P = 0.001) 4 h after consumption of a single 480-mL portion of cranberry juice.
Conclusions: Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity—a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.
Purpose of Review
Our goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic ...agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies.
Recent Findings
The latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy.
Summary
Recurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile.
The risks of missed findings after inadequate bowel preparation are not fully characterized in a diverse cohort. We aimed to evaluate the likelihood of missed polyps after an inadequate preparation ...as assessed by using the Boston Bowel Preparation Scale (BBPS).
In this observational study of prospectively collected data within a large, national, endoscopic consortium, we identified patients aged 50 to 75 years who underwent average-risk screening colonoscopy (C1) followed by a second colonoscopy for any indication within 3 years (C2). We determined the polyp detection rates (PDRs) and advanced PDRs during C2 stratified by C1 BBPS scores.
Among segment pairs without polyps at C1 (N = 601), those with inadequate C1 BBPS segment scores had a higher PDR at C2 (10%) compared with those with adequate bowel preparation at C1 (5%; P = .04). Among segment pairs with polyps at C1 (N = 154), segments with inadequate bowel preparation scores at C1 had higher advanced PDRs at C2 (20%) compared with those with adequate bowel preparation scores at C1 (4%; P = .03). In multivariable analysis, the presence of advanced polyps at C1 (adjusted odds ratio OR 3.5; 95% confidence intervals CIs, 1.1-10.8) but not inadequate BBPS scores at C1 (adjusted OR 1.8; 95% CI, 0.6-5.1) was associated with a significantly increased risk of advanced polyps at C2.
Inadequate BBPS segment scores generally are associated with higher rates of polyps and advanced polyps at subsequent colonoscopy within a short timeframe. The presence of advanced polyps as well as inadequate BBPS segment scores can inform the risk of missed polyps and help triage which patients warrant a timely repeat colonoscopy.
Recent studies have shown mitochondrial dysfunction and increased production of reactive oxygen species in peripheral blood mononuclear cells (PBMCs) and endothelial cells from patients with diabetes ...mellitus. Mitochondria oxygen consumption is coupled to adenosine triphosphate (ATP) production and also occurs in an uncoupled fashion during formation of reactive oxygen species by components of the electron transport chain and other enzymatic sites. We therefore hypothesized that diabetes would be associated with higher total and uncoupled oxygen consumption in PBMCs that would correlate with endothelial dysfunction. We developed a method to measure oxygen consumption in freshly isolated PBMCs and applied it to 26 patients with type 2 diabetes mellitus and 28 non-diabetic controls. Basal (192±47 vs 161±44 pmoles/min, p=0.01), uncoupled (64±16 vs 53±13 pmoles/min, p=0.007), and maximal (795±87 vs 715±128 pmoles/min, p=0.01) oxygen consumption rates were higher in diabetic patients compared to controls. There were no significant correlations between oxygen consumption rates and endothelium-dependent flow-mediated dilation measured by vascular ultrasound. Non-endothelium-dependent nitroglycerin-mediated dilation was lower in diabetics (10.1±6.6 vs 15.8±4.8%, p=0.03) and correlated with maximal oxygen consumption (r = −0.64, p=0.001). In summary, we found that diabetes mellitus is associated with a pattern of mitochondrial oxygen consumption consistent with higher production of reactive oxygen species. The correlation between oxygen consumption and nitroglycerin-mediated dilation may suggest a link between mitochondrial dysfunction and vascular smooth muscle cell dysfunction that merits further study. Finally, the described method may have utility for the assessment of mitochondrial function in larger scale observational and interventional studies in humans.
Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling, through the activity of protein ...kinase C-β (PKCβ) and nuclear factor κB, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus.
We measured protein expression and insulin response in freshly isolated endothelial cells from patients with type 2 diabetes mellitus (n=40) and nondiabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes mellitus (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in nondiabetic subjects but not in diabetic patients (P=0.003), consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients, indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=-0.541, P=0.02). Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor κB activation was higher in diabetes mellitus and was reduced with PKCβ inhibition.
We provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus. Our findings implicate PKCβ activity in endothelial insulin resistance.
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