Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome

ObjectivesThoracic aneurysms are the main cardiovascular complication of Marfan syndrome (MFS) resulting in premature death. MFS has been associated with mutations of the gene encoding fibrillin-1 (FBN1), a major constituent of the elastic fibers. Matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysms but their precise role in MFS is not clear. Doxycycline is a nonspecific MMP inhibitor. The objective of the study was to determine whether docycycline can attenuate matrix degradation and prolong the survival of mice with MFS.MethodsThe study employed a well-characterized animal model of MFS, namely fibrillin-1 under-expressing mice (mgR/mgR mice) that die spontaneously from rupture of the thoracic aorta between 2 to 4 months of age. Mutant and wild type mice were given doxycycline in their drinking water at a concentration designed to provide 100 mg/kg/day beginning at postnatal day (PD) 1, whereas control mice were given water. Treated mice were divided into two groups. One group of animals was followed until death or for 7 months to determine lifespan. In the second group of mice, the ascending thoracic aortas were collected for histological analysis (H&E staining, trichrome staining) and zymography for examining MMP-2 and MMP-9 levels at 6 weeks.ResultsMMP-2 and MMP-9 levels were higher in the thoracic aorta of mgR/mgR mice compared with wild type littermates. Doxycycline-treated mgR/mgR mice lived 132 ± 14.6 days (n = 16) or significantly longer than untreated mutant mice (79 ± 6.7 days, n = 30) (P < 0.01). Connective tissue staining showed that doxycycline treatment decreased elastic fiber degradation in mgR/mgR mice. Furthermore, mgR/mgR mice treated with doxycycline had lower MMP-2 and MMP-9 levels compared with untreated mgR/mgR mice.ConclusionsThis study demonstrates that doxycycline significantly delays aneurysm rupture in MFS-like mice by inhibiting expression of tissue MMP-2 and MMP-9 and thus, degradation of the elastic matrix. The results suggest that MMPs contribute to the progression of thoracic aneurysm in MFS and that doxycycline has the potential to significantly alter the course of the disease.Clinical RelevanceAortic aneurysms are the main cardiovascular complication of Marfan syndrome (MFS) resulting in premature death. β-blockers offer some benefit but do not address the underlying cause of the progressive aortic degradation. Medical treatment that actually targets recently identified pathogenic factors leading to progressive matrix destruction could significantly impact the clinical course of the disease. A recent study using a mouse model of MFS has demonstrated that TGF- β antibodies or the angiotensin II type I receptor (AT1) antagonist losartan can both effectively rescue aneurysm progression. We have found that doxycycline, a nonspecific inhibitor of matrix metalloproteinases (MMPs), can decrease elastin degradation and prolong the lifespan of genetically engineered mice that mimic the human disease process. Based on these results, further testing may be warranted to determine if doxycycline could favorable impact the natural history of Marfan syndrome

Analyzing SOD Activity in Lung Tissue of a Murine Model of Marfan Syndrome

Marfan syndrome is an inherited autosomal dominant disorder caused by a mutation in the Fibrillin-1 gene (FBN1) affecting elastic connective tissue. Marfan syndrome commonly presents with ectopia lentis, aortic dissections, mitral valve prolape, and chronic obstructive pulmonary disease (COPD) in later stages. Patients with Marfan Syndrome are shown to have higher concentrations of reactive oxygen species (ROS) in blood plasma. Increased ROS due to oxidative stress can lead to increased cell damage and death, and have been linked to the formation of aortic dissections5. Superoxide dismutases (SOD) are a class of enzymes that convert harmful oxygen radicals into molecular oxygen and hydrogen peroxide2. Manganese-containing SOD (MnSOD) regulates radical oxygen located in the Mitochondria4. The aim of this study is to explore the role of SOD expression and ROS in relation to COPD found in Marfan syndrome. It is hypothesized that the defect in Fibrillin-1 causes oxidative stress in the lung tissue, which often causes COPD, and it is expected that there would be less SOD activity in tissues from mice with Marfan syndrome. The activity of SOD1 and MnSOD in relation to the oxidative stress that is caused by the deficiency of Fibrillin protein will be determined. To accomplish this, a murine model of Marfan syndrome Fbn1mgR/mgR, mice with a hypomorphic mutation in the Fibrillin-1 gene were compared with homozygous wild type mice. Mice were sacrificed after 1, 4 , and 8 week intervals, and both SOD1 and MnSOD expression was quantified in lung tissue. Results of the study found that there was a significant decrease in SOD1 expression in Marfan mice at the one and four week intervals, but no significant difference in the eight week interval. MnSOD was observed to not have any significant difference in expression in the one and four week Marfan mice, but was expressed at a significantly higher level in the 8 week Marfan mice compared to wild-type controls.https://digitalcommons.unmc.edu/surp2021/1027/thumbnail.jp

Ferromagnetic phase transition for the spanning-forest model (q \to 0 limit of the Potts model) in three or more dimensions

We present Monte Carlo simulations of the spanning-forest model (q \to 0 limit of the ferromagnetic Potts model) in spatial dimensions d=3,4,5. We show that, in contrast to the two-dimensional case, the model has a "ferromagnetic" second-order phase transition at a finite positive value w_c. We present numerical estimates of w_c and of the thermal and magnetic critical exponents. We conjecture that the upper critical dimension is 6.Comment: LaTex2e, 4 pages; includes 6 Postscript figures; Version 2 has expanded title as published in PR

Critical speeding-up in a local dynamics for the random-cluster model

We study the dynamic critical behavior of the local bond-update (Sweeny) dynamics for the Fortuin-Kasteleyn random-cluster model in dimensions d=2,3, by Monte Carlo simulation. We show that, for a suitable range of q values, the global observable S_2 exhibits "critical speeding-up": it decorrelates well on time scales much less than one sweep, so that the integrated autocorrelation time tends to zero as the critical point is approached. We also show that the dynamic critical exponent z_{exp} is very close (possibly equal) to the rigorous lower bound \alpha/\nu, and quite possibly smaller than the corresponding exponent for the Chayes-Machta-Swendsen-Wang cluster dynamics.Comment: LaTex2e/revtex4, 4 pages, includes 5 figure

Dynamic critical behavior of the Chayes-Machta-Swendsen-Wang algorithm

We study the dynamic critical behavior of the Chayes-Machta dynamics for the Fortuin-Kasteleyn random-cluster model, which generalizes the Swendsen-Wang dynamics for the q-state Potts model to noninteger q, in two and three spatial dimensions, by Monte Carlo simulation. We show that the Li-Sokal bound z \ge \alpha/\nu is close to but probably not sharp in d=2, and is far from sharp in d=3, for all q. The conjecture z \ge \beta/\nu is false (for some values of q) in both d=2 and d=3.Comment: Revtex4, 4 pages including 4 figure

Outcomes of Aortic Surgery for Abdominal Aortic Graft Infections

Background: Literature on postoperative outcomes following aortic surgery for aortic graft infection (AGI) is limited by relatively small sample sizes, resulting in lack of national benchmarks for quality of care. We report in-hospital outcomes following abdominal aortic surgery for AGI and identify factors associated with postoperative complications using the Nationwide Inpatient Sample (NIS) database. Methods: Patients who underwent aortic graft resection for AGI were identified from the 2002 to 2008 NIS database, a multicenter database capturing 20% of all US admissions. Multivariable logistic regression analyses were performed. Results: Among 394 patients (men: 73.4%) who underwent abdominal aortic surgery for AGI, 53% of the admissions were emergent/urgent. A significant trend for decreasing number of abdominal aortic surgery for AGIs per year was observed (Pearson r correlation: -.96; P = .0006). Over the same time span, a significant correlation was also seen with decrease in open and increase in endovascular aortic aneurysm repairs in the NIS database. In-hospital rates of overall postoperative morbidity and mortality were 68.3% and 19.8%, respectively. In-hospital rates of postoperative respiratory failure, renal failure, and cardiac arrest were 35.5%, 14.2%, and 8.9%, respectively. Median length of stay was 26 days, with median hospital charges being US$184 162. On multivariable analysis, increase in age per year (odds ratio [OR] 1.07; 95% confidence interval [CI]: 1.03-1.12) was independently associated with postoperative morbidity, while higher hospital volume for this procedure was protective (OR: 0.71; 95% CI: 0.56-0.89). No preoperative factors were independently associated with postoperative mortality. Conclusion: Incidence of abdominal aortic surgery for AGI has progressively declined over the span of our study in association with decreased open and increased endovascular aortic aneurysm repairs. Aortic surgery for AGI is associated with very high morbidity and mortality rates along with prolonged lengths of stay and elevated hospital charges. The outcomes of operations for AGI are better in younger patients and higher volume hospitals

MMP-9 Microsatellite Polymorphism and Susceptibility to Carotid Arteries Atherosclerosis

Objective— The aims of this study were to compare a microsatellite polymorphism (PM) of matrix metalloproteinase (MMP)-9 in patients with carotid atherosclerosis and control population, and to assess the relationship between this PM and plaque structure. Methods and Results— One hundred fifty patients referring to vascular diagnostic centers for suspected carotid atherosclerosis (at ultrasound examination: 110 positive, 40 negative) and controls (n=110) have been genotyped for MMP-9 PM. After controlling for risk factors, allelic and genotype frequencies were significantly different among the groups, with significant prevalence of long microsatellites in patients with carotid atherosclerosis. Long microsatellites (settled as 22 to 27 repeats) were associated with carotid atherosclerosis (odds ratio [OR], 5.2; 95% confidence interval [CI], 2.9 to 9.2), compared with controls; an independent case control study on patients with coronary atherosclerosis confirmed such result. Binary logistic regression showed that hypertension, long microsatellites in MMP-9 PM and smoking habits were variables accounting for the difference between ultrasound-positive patients and controls. Long microsatellites were also associated to plaques with thin fibrous cap and echolucent core (OR, 13.1; 95% CI, 1.6 to 100). These alleles were slightly more represented in female patients (χ 2 test=0.019; OR, 2.7; 95% CI, 1.2 to 6) but not associated with other risk factors. Plasma MMP-9 levels were related neither to MMP-9 PM nor to plaque type, and were related to gender and extension of atherosclerosis in carotid arteries. Conclusions— The number of repeats (≥22 CA) in the microsatellite of MMP-9 promoter, but not MMP-9 plasma levels, is associated to carotid atherosclerosis and particularly to plaques with a thin fibrous cap

Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell–deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow–derived mast cells from WT or TNF-α–/– mice, but not from IL-6–/– or IFN-γ–/– mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms

Dynamic Critical Behavior of the Chayes-Machta Algorithm for the Random-Cluster Model. I. Two Dimensions

We study, via Monte Carlo simulation, the dynamic critical behavior of the Chayes-Machta dynamics for the Fortuin-Kasteleyn random-cluster model, which generalizes the Swendsen-Wang dynamics for the q-state Potts ferromagnet to non-integer q \ge 1. We consider spatial dimension d=2 and 1.25 \le q \le 4 in steps of 0.25, on lattices up to 1024^2, and obtain estimates for the dynamic critical exponent z_{CM}. We present evidence that when 1 \le q \lesssim 1.95 the Ossola-Sokal conjecture z_{CM} \ge \beta/\nu is violated, though we also present plausible fits compatible with this conjecture. We show that the Li-Sokal bound z_{CM} \ge \alpha/\nu is close to being sharp over the entire range 1 \le q \le 4, but is probably non-sharp by a power. As a byproduct of our work, we also obtain evidence concerning the corrections to scaling in static observables.Comment: LaTeX2e, 75 pages including 26 Postscript figure