scholarly journals 3204 Renin-Angiotensin System Inhibitors Do Not Improve Survival in Fibrillin-1 Hypomorphic Mice with Established Aortic Aneurysm

2019 ◽  
Vol 3 (s1) ◽  
pp. 112-113
Author(s):  
Mary Burchett Sheppard ◽  
Jeff Zheying Chen ◽  
Debra L. Rateri ◽  
Jessica J. Moorleghen ◽  
Mackenzie Weiland ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Marfan Syndrome ◽  
Renin Angiotensin System ◽  
Aortic Diameter ◽  
Wild Type ◽  
Aortic Dilation ◽  
Angiotensin System ◽  
Male And Female ◽  
Significant Difference ◽  
Fibrillin 1

OBJECTIVES/SPECIFIC AIMS: Drugs to attenuate aortic growth are usually not initiated in patients with Marfan syndrome until aortic dilation is already present. Therefore, we measured the impact of drugs (the renin-angiotensin system inhibitors losartan and enalapril) on survival and thoracic aortic growth in a mouse model of Marfan syndrome when extensive aortic dilation was already present. METHODS/STUDY POPULATION: Male and female fibrillin-1 hypomorphic (FBN1 mgR/mgR) mice (n=10-12/group) were stratified into treatment groups by aortic diameter at 6 weeks of age to ensure an equivalent average aortic diameter in each group at the start of the study. Osmotic mini pumps filled with PBS (vehicle), enalapril (2 mg/kg/d), or losartan (20 mg/kg/d) were implanted subcutaneously into mice after stratification. Mini pumps infusing drug or vehicle were replaced every 4 weeks for a total duration of 12 weeks. Wild type littermates (n=10) were infused with PBS as a negative control to the Marfan mouse model. Ascending aortic diameters from male and female FBN1 mgR/mgR mice and their wild type littermates were assessed by ultrasound every 4 weeks from 6 to 18 weeks of age. Aortic diameters were measured luminal edge to luminal edge during diastole. RESULTS/ANTICIPATED RESULTS: 6 week old FBN1 mgR/mgR mice exhibited significantly dilated ascending thoracic aortas at study initiation compared to their wild type sex-matched littermates (in males: FBN1 mgR/mgR = 1.87 +/− 0.07mm, wild type = 1.23 +/− 0.07mm; p <0.001) (in females: FBN1 mgR/mgR = 1.56 +/− 0.07mm, wild type = 1.18 +/− 0.07mm; p <0.001). Baseline mortality of FBN1 mgR/mgR mice infused with PBS was 36% in male and 22% in female mice at the time of study termination. Within sex-matched mgR littermates, there was no significant difference in survival between groups treated with PBS, enalapril, or losartan after 12 weeks (p=0.224 for males, p=0.094 in females). In the same groups, no significant difference in maximum ascending aortic diameter was detected after treatment for 12 weeks (in males: PBS=2.69 +/− 0.19 mm, enalapril=2.04 +/− 0.27 mm, losartan=2.42 +/− 0.28 mm; p=0.24) (in females: PBS = 1.92 +/− 0.13, enalapril=1.89 +/− 0.31, losartan=1.98 +/− 0.17; p=0.86). Furthermore, aortic diameters in the FBN1 mgR/mgR mice were found to demonstrate sexual dimorphism. DISCUSSION/SIGNIFICANCE OF IMPACT: This research shows that losartan is not effective when administered after significant thoracic aortic dilation has already occurred in FBN1 mgR/mgR mice. This has important translational implications because losartan is usually not started in patients with Marfan syndrome until significant aortic dilation is already present. Therefore, more research needs to be done to determine the critical time period within which this medicine will be effective if given to patients. In addition, this research demonstrates that male FBN1mgR/mgR mice have a significantly larger aortic diameter than female FBN1mgR/mgR mice. This sexual dimorphism has recently been observed in patients with Marfan syndrome as well. Additional studies for understanding the mechanism underlying this sexual dimorphism have the potential to elucidate new therapeutic approaches for aortic disease.

scholarly journals 2464 Sexual dimorphism in a mouse model of syndromic thoracic aortic aneurysm

2018 ◽  
Vol 2 (S1) ◽  
pp. 27-27
Author(s):  
Zheying Chen ◽  
Alan Daugherty ◽  
Mary Sheppard
Keyword(s):  
Extracellular Matrix ◽  
Sexual Dimorphism ◽  
Mouse Model ◽  
Aortic Aneurysms ◽  
Pcr Analysis ◽  
Wild Type ◽  
Aortic Dilation ◽  
Male And Female ◽  
Thoracic Aortic Aneurysms ◽  
Male Sex

OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24±0.43 vs. 1.57±0.22 mm; p=0.002), while there were no significant differences between sexes of wild type littermates (1.29±0.13 vs. 1.23±0.08 mm; p=0.71). Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation (2.76 vs. 1.85 breaks/ 100 µm aorta; p=0.03). DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.

Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

2006 ◽  
Vol 291 (2) ◽  
pp. R383-R390 ◽  
Author(s):  
Licy L. Yanes ◽  
Damian G. Romero ◽  
Joshua W. Iles ◽  
Radu Iliescu ◽  
Celso Gomez-Sanchez ◽  
...  
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Spontaneously Hypertensive Rats ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Male And Female ◽  
Spontaneously Hypertensive ◽  
Renin Angiotensin

In young adult spontaneously hypertensive rats (SHR), mean arterial pressure (MAP) is higher in males than in females and inhibition of the renin-angiotensin system (RAS) eliminates this sex difference. After cessation of estrous cycling in female SHR, MAP is similar to that in male SHR. The purpose of this study was to determine the role of the RAS in maintenance of hypertension in aging male and female SHR. At 16 mo of age, MAP was similar in male and female SHR (183 ± 5 vs. 193 ± 8 mmHg), and chronic losartan (40 mg·kg−1·day−1 po for 3 wk) reduced MAP by 52% (to 90 ± 8 mmHg, P < 0.05 vs. control) in males and 37% (to 123 ± 11 mmHg, P < 0.05 vs. control) in females ( P < 0.05, females vs. males). The effect of losartan on angiotensin type 1 (AT1) receptor blockade was similar: MAP responses to acute doses of ANG II (62.5–250 ng/kg) were blocked to a similar extent in losartan-treated males and females. F2-isoprostane excretion was reduced with losartan more in males than in females. There were no sex differences in plasma renin activity, plasma angiotensinogen or ANG II, or renal expression of AT1 receptors, angiotensin-converting enzyme, or renin. However, renal angiotensinogen mRNA and protein expression was higher in old males than females, whereas renal ANG II was higher in old females than males. The data show that, in aging SHR, when blood pressures are similar, there remains a sexual dimorphism in the response to AT1 receptor antagonism, and the differences may involve sex differences in mechanisms responsible for oxidative stress with aging.

TAMI-54. SEXUAL DIMORPHISM IN IRON ACQUISITION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi209-vi209
Author(s):  
Bhavyata Pandya ◽  
Becky Slagle Webb ◽  
Brad Zacharia ◽  
Justin Lathia ◽  
Joshua Rubin ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Iron Uptake ◽  
Iron Transport ◽  
Iron Acquisition ◽  
Wild Type ◽  
Binding Studies ◽  
Orthotopic Mouse Model ◽  
Male And Female ◽  
Significant Difference

Abstract Sexual dimorphism in incidence and the clinical outcomes of Glioblastoma (GBM) has been reported, however, our knowledge of contributing biological mechanisms is limited. Iron acquisition is key to robust tumor growth. Upregulation of Transferrin (TF, iron transport protein)/Transferrin receptor (TFR) is critical for found in multiple different cancers, specifically, we have identified H-ferritin (FTH1) as a contributor to iron transport and protection in cancer stem cells. To interrogate brain tumor iron uptake mechanisms,we performed binding studies on homogenized samples of human male and female GBM tissue samples using 125I labeled TF and FTH1. Tumors from males had a ̴ 3.8-fold increased binding of both proteins compared to tumors from females. We interrogated iron uptake in a syngeneic orthotopic mouse model (GL261 cells) using male and female mice. After the tumors were established, radioactive 125I labeled TF and FTH1 proteins were injected retro-orbitally in the mice. After 24 hours, tumors wereremoved, and analyzed for TF and FTH1 uptake. Male tumors showed an increased uptake, of ̴ 3.2-fold, as compared to female tumors. There was no significant difference in TF uptake between male and female tumors nor between tumor and matched non-tumor brain tissue. We next queried role of FTH1 in the context of sexual dimorphism in GBM in a FTH1+/- mouse strain developed in our laboratory. Survival was monitored in the mice which were injected with GL261 cells at 3 months. Male mice that had reduced expression of FTH1 had poorer survival as compared to the male wild type controls whereas wild type and FTH+/- females had no major differences in survival outcomes. In summary, this study demonstrates sexual dimorphism in iron acquisition in GBM and animal models further suggesting a pathophysiological role of iron metabolism in GBM development and its possible role in prognosis.

Abstract 18473: Rates and Risk Factors for Faster Aortic Root Growth in Pediatric Patients with Marfan Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nitya Viswanathan ◽  
Claudia Pedroza ◽  
Shaine A Morris
Keyword(s):  
Aortic Dissection ◽  
Root Growth ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Scoliosis Surgery ◽  
Z Score ◽  
Aortic Dilation ◽  
Significant Difference ◽  
Over Time ◽  
Infantile Type

Background: Marfan Syndrome (MS) is associated with progressive aortic dilation and aortic dissection. Aortic dissection is typically preceded by aortic dilation. The goal of this study is to identify factors associated with faster rates of aortic root dilation in children with MS. Methods: Patients undergoing serial transthoracic echocardiograms (TTE) with MS were retrospectively identified from an institutional database. Those with >2 TTEs over 1 year apart and <21 years of age at first TTE were included. TTEs performed after aortic surgery were excluded. Using multivariable longitudinal linear regression analysis, sex, medication, presence of ectopia lentis, need for scoliosis surgery and infantile type of MS were evaluated for associations with rate of change in aortic root dimension and aortic root z-score over time. Results: Of 240 patients with MS, 146 were included. Median age at first TTE was 8.1 yrs (range 0-20.9 years), median length of follow up 6.5 years (range 1.0-20.1 years), and median number of studies was 8 (range 2-25). Sixty-one percent were male. Of the 146 patients, 123 (84%) were documented to be on medical therapy: 14 angiotensin receptor blocker (ARB), 66 B-Blocker (BB), 10 prior history of both, 5 BB+ARB, 27 were in the Pediatric Heart Network medication trial, 1 ACE inhibitor. Sixteen patients underwent root replacement surgery at a median age of 14.6 years (range 1.8-24). No patients had aortic dissection. Three patients had infantile MS. All of these patients underwent root replacement at 1.8, 2 and 4 years of age. Two underwent subsequent aortic root replacement at 6 and 8 years old. Mean rate of aortic root growth in the cohort was 0.12cm/year, and mean change in z-score was 0.02/year (p=0.23 compared to expected rate of no change). The only variable associated with faster root growth was infantile MS (1.3cm/year, p<0.001; z-score change of 6.9/year, p<0.001). There was no significant difference in the rate of aortic root growth between patients who received therapy with BB vs. ARB vs. BB+ARB. Conclusions: Children with MS did not have a significant change in aortic root z-score over time, and the only factor associated with more rapid aortic root growth was infantile type MS.

Abstract 308: Cardiac Cycle Affects Ultrasound Measurements of Ascending Aortic Diameter in a Marfan Mouse Model

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Zheying Chen ◽  
Hisashi Sawada ◽  
Debra Rateri ◽  
Alan Daugherty ◽  
Mary Sheppard
Keyword(s):  
Cardiac Cycle ◽  
Interobserver Variability ◽  
Innominate Artery ◽  
Aortic Diameter ◽  
Ultrasound Images ◽  
Anatomical Landmarks ◽  
Wild Type ◽  
Ultrasound Measurements ◽  
Fibrillin 1 ◽  
Ascending Aortic Diameter

Objective: Ultrasound measurements of aortic diameter are a common endpoint in preclinical studies. However, there is a lack of standardization in both image capture and analysis. For our study, we developed a standardized protocol for measuring ascending aortic diameter and examined effects of cardiac cycle in wild type and fibrillin-1 hypomorphic (FBN mgR/mgR ) mice. Methods and Results: Twelve week old male and female FBN mgR/mgR mice were anesthetized and maintained at a heart rate of 450-550 beats per minute. Ultrasound images were captured using a Vevo 2100 system with a 40MHz tranducer. Images captured were standardized according to two anatomical landmarks: the innominate artery branchpoint and aortic valves. The largest luminal ascending aortic diameter between the sinotubular junction and the innominate artery were measured in mid-systole and end-diastole by two blinded, independent observers. Aortic diameters were significantly different (p<0.05) when comparing systole and diastole within gender and genotype. Interestingly, wild-type male (n=4) and female (n=3) mice exhibited a 19% and 15% expansion of the ascending aorta respectively during systole compared to diastole. This difference was not recapitulated in either male (n=6) or female (n=5) FBN mgR/mgR mice (4% expansion in both; p<0.05 vs wild-type). Agreement between observers was excellent (R^2 = 0.99) but interobserver variability was a mean of .09 mm (%CV = 5%) Conclusion: As expected, there is a difference in aortic diameters between wild-type and FBN mgR/mgR mice. Luminal aortic diameters in FBN mgR/mgR vs wild-type mice of both genders are affected by cardiac cycle. Mid-systolic aortic expansion in wild-type vs FBN mgR/mgR mice were different. Error introduced by interobserver variability impacts ascending aortic measurements. Altogether, these phenomena may confound analyses of aortic dilation in FBN mgR/mgR mice, especially when studying interventions with modest effect sizes.

Early Renin-angiotensin System Blockade Improved Short-term and Longterm Renal Outcomes in Systemic Lupus Erythematosus Patients with Antiphospholipid-associated Nephropathy

2018 ◽  
Vol 45 (5) ◽  
pp. 655-662 ◽  
Author(s):  
Cai Yue ◽  
Guanhong Li ◽  
Yubing Wen ◽  
Xuemei Li ◽  
Ruitong Gao
Keyword(s):  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Renin Angiotensin System ◽  
Systemic Lupus ◽  
Short Term ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Raas Blockade ◽  
Significant Difference ◽  
Kidney Disease Progression

Objective.To investigate the renal protective effects of early renin-angiotensin-aldosterone system (RAAS) blockade with renin-angiotensin system inhibitors (RASI) in systemic lupus erythematosus (SLE) patients with antiphospholipid-associated nephropathy (aPLN).Methods.Medical data of 57 SLE patients with biopsy-proven aPLN were analyzed. Early RAAS blockade was defined as administration of RASI within 3 months after kidney biopsy and continued for ≥ 12 months.Results.There was no significant difference in demographic data, laboratory findings, and renal histology by the time of kidney biopsy, except that the RASI group had higher proteinuria levels vs the non-RASI group [5.2 (2.8–8.8) vs 1.9 (0.6–2.8) g/d, p = 0.005, respectively] and higher prevalence of hypertension (75% vs 29%, p = 0.001, respectively). No significant difference between the 2 groups was observed in estimated glomerular filtration rate (eGFR), mean arterial pressure, and proteinuria level at 12 months after kidney biopsy. The improvement ratio of eGFR at 12 months was significantly higher in the RASI group versus the non-RASI group [26% (−5 to 86) vs −2% (−20 to 20), p = 0.028, respectively], and the rate of change in eGFR beyond 12 months was similar between the 2 groups. During a mean followup of 80 months, 4 (23%) patients in the non-RASI group and 3 (8%) patients in the RASI group developed kidney disease progression. Early RAAS blockade significantly decreased the risk of kidney disease progression [HR = 0.11 (0.02–0.59); p = 0.010]. Proteinuria and hypertension controls were similar between the 2 groups.Conclusion.Early RAAS blockade improved the short-term and longterm renal outcomes in SLE patients with aPLN. The renal protective effect of RASI was independent of its antihypertensive and antiproteinuric effects.

scholarly journals Losartan Increases Survival of the Fbn1mgR/mgR Mouse Model of Marfan Syndrome in an Age-Dependent Manner

2021 ◽  
Author(s):  
Jeffrey D. Smith ◽  
Jeff Z. Chen ◽  
Rebecca Phillips ◽  
Alan Daugherty ◽  
Mary B. Sheppard
Keyword(s):  
Marfan Syndrome ◽  
Angiotensin Receptor Blockers ◽  
Primary Objective ◽  
Dependent Manner ◽  
Wild Type ◽  
Age Dependent ◽  
Fibrillin 1 ◽  
Receptor Blockers ◽  
To Receive ◽  
Overall Mortality

AbstractClinical trials investigating angiotensin receptor blockers (ARB) for attenuation of thoracic aortic aneurysm in people with Marfan syndrome have demonstrated variable efficacy. The primary objective of this study was to determine whether the age of mice at the time of losartan initiation affected mortality in fibrillin-1 hypomorphic (Fbn1mgR/mgR) mice. Male (n=40) and female (n=28) Fbn1mgR/mgR mice were randomized to receive losartan in drinking water (0.6 g/L) starting at either 24 or 50 days of age. Controls included Fbn1mgR/mgR mice (20M, 14F) and wild type (15M, 15F) littermates who were not administered the drug. Mortality of Fbn1mgR/mgR males receiving losartan at postnatal day 24 (P24) was not different from wild type controls (p=0.138). Survival of Fbn1mgR/mgR males administered losartan at P50 was not different compared to Fbn1mgR/mgR males receiving no drug (p=0.194) and decreased compared to wild type mice (p=0.002). Survival analysis after P50 demonstrated increased survival of Fbn1mgR/mgR males administered losartan at P50 compared to Fbn1mgR/mgR mice receiving no drug (p=0.017). Age is a critical variable that affects the therapeutic efficacy of losartan in male Fbn1mgR/mgR mice. Since overall mortality in female Fbn1mgR/mgR mice was lower than in male Fbn1mgR/mgR mice, a survival benefit with losartan was not detected in females.

scholarly journals Nasal index among Students of People’s Dental College and Hospital

2019 ◽  
Vol 1 (1) ◽  
pp. 21-27
Author(s):  
Mangesh Bajracharya ◽  
Samjhana Sharma
Keyword(s):  
Ethnic Identity ◽  
Sexual Dimorphism ◽  
Female Students ◽  
Baseline Data ◽  
Craniofacial Surgery ◽  
Male And Female ◽  
Size And Shape ◽  
Gender Differentiation ◽  
Significant Difference ◽  
The Mean

Introduction: Nasal anthropometry is a study that deals with the measurements of the proportion, size, and shape of the nose. The nasal index is considered as one of the major landmarks for craniofacial surgery, gender differentiation, and ethnic identity. This study is aimed to provide baseline data of the nasal index of Nepalese people and to assess the gender variation which will be of clinical, surgical interest in rhinology and craniofacial prosthetic purpose. Methods: BDS students from 17 to 25 years with various ethnicity were included in the study. A total of 160 students with an equal number of male and female students was included. Nasal parameters were measured and the nasal index was calculated for each student. Result: The mean nasal index was 78.03±7.07 suggesting Mesorrhine type of nose. The nasal width and height show statistically significant differences whereas there was no significant difference found between the nasal indices of male and female students. Hill Janajati showed the highest nasal index followed by Newar, Brahmin and Chettri; and Others. Conclusion: The study concludes the type of nose has an effect on gender when compared between the sex but the nasal index calculated to have a little contribution to sexual dimorphism. Mesorrhine nose was found to be most frequent. Among the population, Hill Janajati showed the highest nasal index. We recommend further study to compare the nasal index of various ethnical groups of the Nepalese population. Keywords: Anthropometry, Mesorrhine, Nasal Index

scholarly journals Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1 C1041G/+ Mice

2021 ◽  
Author(s):  
Jeff Z. Chen ◽  
Hisashi Sawada ◽  
Dien Ye ◽  
Yuriko Katsumata ◽  
Masayoshi Kukida ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Antisense Oligonucleotide ◽  
Thoracic Aortic Aneurysm ◽  
Renin Angiotensin System ◽  
Ascending Aorta ◽  
Ang Ii ◽  
Angiotensin Receptor ◽  
Aortic Dilation ◽  
Angiotensin System ◽  
Renin Angiotensin

Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.

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