Background: Studies have indicated an association between Alzheimer’s disease (AD) and increased risk of developing cardiovascular complications. Lifestyle modifiable factors, such as exercise and diet, are known to prevent cardio-cerebral disease. Recent studies demonstrate that hearts from early onset triple-transgenic AD mice exhibit pathologies, but it is not clear whether cardiovascular function is altered in this model. Methods: In this study, we measured in vivo cardiovascular function in 7-month-old male 3xTg mice and age-matched wild-type (WT) mice using high-frequency high-resolution ultrasound imaging. Results: Our findings indicated that aortic root measurements and interventricular septal dimensions were similar in 3xTg and wild-type mice. Systolic function, expressed as ejection fraction and fractional shortening, were decreased in 3xTg mice. Late (A) ventricular filling velocities, the early/atrial (E/A) ratio, and mitral valve deceleration time, all indices of diastolic function, were increased in 3xTg mice compared to WT mice. Treadmill exercise training and resveratrol supplementation in the diet for 5 months improved ejection fraction, fractional shortening, and restored diastolic deceleration times. Pulse wave velocity was ~33% higher in 3xTg, and accompanied by a significant increase in elastin fiber fragmentation within the aortic wall, which was associated with decrease in elastin content and fiber length. Aortic wall and adventitia thickness were increased in 3xTg mice compared to the WT group. Exercise training and resveratrol supplementation, or both, improved overall aortic morphology with no change in pulse wave velocity. Conclusion: Taken together, the results indicate that the aberrations in cardiac function and aortic elastin morphology observed in the 3xTg mouse model of AD can be prevented with exercise training and treatment with resveratrol. The benefits of regular exercise training and resveratrol supplementation of heart and aortic structure in the 3xTg mouse support the value of healthy lifestyle factors on cardiovascular health.
IntroductionAlzheimer's disease (AD) is the most common form of dementia in the United State with age and sex being the biggest risk factors. In addition, individuals with cardiovascular disease (CVD) have an increased risk for development of AD. A link between AD and CVD is apolipoprotein E (APOE), a protein that primarily functions to traffic lipids in the body and brain. Individuals with a particular allele of APOE, APOE4, are at increased risk for developing both CVD and AD/dementia. CVD remains the leading killer of both women and men in the United States. By the age of 65, women have 1 in 6 chance of developing AD compared to a 1 in 11 chance for men. Therefore, out of the 5 million people living with Alzheimer's in the U.S., 3.2 million are women. Because of these differences, this study was designed to assess the effect of the hAPOE4 genotype on carotid artery (CA) function, thoracic aorta (TA) function, and cardiac (C) function in young and aged hAPOE4.PurposeWe hypothesize that female mice expressing hAPOE4 will exhibit augmented age related decline in C, TA and CA function than aged matched male hAPOE4 mice.MethodsIn vivo investigation of C, TA ad CA structure/function was assessed in young (4±1months) and aged (18±2 months), female and male, hAPOE4 mice using high ‐ resolution ultrasound (U/S) system. In addition, blood pressure (BP) was determined using the tail‐cuff method. All U/S and BP values were collected under isoflurane anaesthesia. Results were considered significant at p<0.05.ResultsIn this study, young and old, female and male hAPOE4 mice exhibited similar bodyweights. CA structure and function was assessed by wall thickness (WT) and pulse wave velocity (PWV) respectively. Both female and male hAPOE4 mice displayed an age‐related increase in PWV (p<0.05), but only the female APOE4 mice displayed an age related increase in CA wall thickness (WT) (p<0.05). Female and male hAPOE4 mice exhibited an age‐related increase in TA PWV (P<0.05), but measurements of aortic structures: aortic annulus, sinus of valsalva, and sinotubular junction showed no significant sex or age related change. Interestingly, except for a modest increase in mitral valve deceleration time with age in male hAPOE4 mice, there was no effect of age or sex on cardiac parameters assessed by U/S (e.g., cardiac output, ejection fraction, stroke volume, etc.). Finally, blood pressures were similar in female and male, young and old hAPOE4 mice with the only exception being an elevated pulse pressure in young male hAPOE4 mice vs young female APOE4 mice (p<0.05).Summary/ConclusionThese preliminary data suggest that female and male, hAPOE4 mice, exhibit age‐related changes in TA and CA structure and function. Additional studies will be needed to determine whether hAPOE4 mice exhibit structural and/or functional changes similar to that seen in women and men.Support or Funding InformationMidwestern University/Arizona Alzheimer's Consortium (DME, JVE, CJ, JP, TV, BJ), Biomedical Sciences start‐up funds (DME)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Marfan syndrome (MFS) is an autosomal dominant inherited disease that affects the connective tissue of large vessels throughout the human body. MFS is caused by mutations in the FBN1 gene which encodes for fibrillin‐1, a major component of extracellular microfibrils and acts as a scaffolding protein for elastin deposition, and allows for the formation of elastic fibers in the extracellular matrix of large arteries. The loss of aortic wall structural integrity leads to cardiovascular manifestations of MFS, which include the dilation of the aortic root that can lead to dissection and rupture. Previous studies have shown that the activity of endothelial nitric oxide (eNOS) has decreased in the aortic wall leading to endothelial dysfunction in MFS mice. However, we have been able to show that despite an obvious decrease in eNOS activity, the basal NO level in the aortic tissue is significantly higher in MFS mice aorta. Therefore, we aim to further determine the role that inducible nitric oxide synthase (iNOS) may play in MFS aneurysm pathogenesis by creating a MFS mouse lacking iNOS expression. In this study, wild type C75BL/6, MFS (FBN +/−) and MFS mice lacking iNOS expression (FBN+/−, iNOS−/−) were subjected to high resolution, high frequency ultrasound imaging at the age of 3 and 6 months to evaluate various cardiac and aortic parameters including aortic diameter, pulse wave velocity, cardiac ejection fraction & stroke volume, left ventricular wall thickness and mass and mitral valve early and atrial velocities (E/A) ratio. Our data shows that aortic root diameters at the aortic annulus and sinus of Valsalva, aortic pulse wave velocity, and mitral valve early velocity were greater in 3‐month old MFS mice when compared to control and MFS mice lacking iNOS expression, indicating a significant increase in aortic wall stiffness in MFS mice aorta. At 6 months of age, mitral valve early and atrial velocities and E/A ration were significantly decreased in MFS mice compared to controls and MFS mice lacking iNOS expression. In addition, measurements for aortic annulus diameter, ejection fraction, fractional shortening were markedly increased in 6‐month old MFS mice as compared to control and MFS mice lacking iNOS expression. These findings indicate that inhibition of iNOS may have some protective effects in the cardiovascular system in MFS mice, and therefore, providing valuable information about the potential therapeutic value of iNOS inhibition on cardiac and aortic function and structure in the mouse model of MFS associated aortic aneurysm.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin‐1 gene leading to various complications in multiple organs. However, aortic aneurysm is considered as the most life‐threatening complications that may lead to aortic dissection, rupture, and sudden death. Previous studies have shown that transforming growth factor β (TGF‐β) and angiotensin II type 1 receptor (ATII/AT1R) signaling play important roles during the progression of MFS aneurysm. Interestingly, both pathways are shown to be regulated by caveolin‐1 (Cav‐1), a structural protein within caveolae, which is highly expressed in vascular smooth muscle and endothelial cells. Studies in Cav‐1 knock‐out mice have reported that Cav‐1 is required for normal ATII/AT1R signalling, while having inhibitory effects on TGF‐β pathway and endothelial nitric oxide (eNOS) activity. Considering the complexity of caveolae and CAV‐1 regulatory functions, we propose to investigate the effects of caveolae (CAV‐1) disruption by the cholesterol depleting agent methyl‐β‐cyclodextrin (MβCD) on the progression of aortic aneurysm in a mouse model of MFS. Four‐week old MFS (Fbn1C1039G/+) and control C57BL/6 mice received intra‐peritoneal injection of MβCD (500 mg/kg) twice a week, and cardiac and aortic structure and function were measured at 3 and 6 months of age using Vevo 2100 high resolution ultra sound imaging system (FUJIFILM VisualSonics). Measurements for aortic annulus, sinus of Valsalva, sinotubular junction diameters, and pulse wave velocity showed an increase in MFS mice at 3 and 6 months of age as compared to control; all these effects were exacerbated in MFS mice treated with MβCD, indicating that disruption of caveolae structure in MFS mice has negative impact on aortic wall structure and function. Furthermore, the dimensions of the left ventricle were also evaluated by the measurements of interventricular septum in systole and diastole. Cardiac function was evaluated measuring the cardiac output, stroke volume, ejection fraction, which showed no difference in MFS and control mice in the presence or absence of MβCD treatment. Early and atrial ventricular filling velocities were decreased in MFS mice at the age of 3 and 6 months as compared to controls. However, MβCD treatment resulted in an increase in both early and atrial velocities in MFS mice. Using the tail‐cuff method we also measured the blood pressure of these animals. The measurements showed higher systolic and diastolic values in control and MFS groups treated with MβCD, confirming that caveolae has an inhibitory effect on eNOS activity in mice. This study provides insights into the role that caveolae may play during the progression of aortic aneurysm in MFS mice, and warrant further investigation into the potential value of CAV‐1 as a therapeutic target in MFS associated aortic aneurysm.Support or Funding InformationThis study is supported by funding from The Marfan Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Marfan syndrome (MFS) is a systemic connective tissue disorder due to mutations in the fibrillin‐1 gene. Previous studies have shown that transforming growth factor β (TGF‐β) and angiotensin II type 1 receptor (ATII/AT1R) signalling play important roles during the progression of MFS aneurysm. Interestingly, both pathways are shown to be regulated by caveolin‐1 (Cav‐1), a structural protein within caveolae, a lipid rich membrane invagination with significant presence in vascular smooth muscle and endothelial cells. Previous studies have also shown that Cav‐1 can negatively regulate endothelial nitric oxide synthase (eNOS), the main enzyme responsible for vasodilation in blood vessels. In addition, it has been shown that eNOS overexpression and activation can play a protective role in MFS aneurysm. Considering the complexity of Cav‐1 regulatory functions and its impact on eNOS function, we aimed to investigate potential roles that Cav‐1 may plan during the progression of MFS‐associated aortic aneurysm in a well‐established mouse model.Four‐week old control C57BL/6 (Fbn1+/+) and MFS (Fbn1C1039G/+) received intra‐peritoneal injections (500mg/kg) of cholesterol depleting agent methyl‐β‐cyclodextrin (MβCD) with the aim of systemic disruption of caveolae formation. Cardiac and aortic structure/function was measured at 3 & 7 months of age using Vevo 2100 ultrasound imaging system. Measurements for aortic annulus, sinus of Valsalva and sinotubular junction showed an increase in MFS at 7 months as compared to controls. Measurements for pulse wave velocity (PWV), a reliable proxy for aortic wall stiffness, showed an increase in 3‐ and 7‐month old MFS mice as compared to controls. All these effects were exacerbated in MFS mice treated with MβCD. Cardiac function was evaluated measuring the cardiac output, stroke volume, ejection fraction, which showed no difference in MFS and control mice in the presence or absence of MβCD treatment. Early ventricular filling velocity and E/A ratio were decreased in MFS mice at 3 and 7 months, with no significant difference observed in the atrial filling velocity among experimental groups. Measurements for blood pressure showed higher systolic values in 7‐month old treated MFS mice as compared to 3‐month old groups. In a complementary set of experiments, we injected control and MFS mice intraperitoneally with vehicle control or a cell‐permeable Cav‐1 scaffolding domain (CSD) peptide, amplifying the inhibitory effects of Cav‐1 on eNOS in these mice. Interestingly, treatment with CSD improved aortic wall elastin fragmentation and wall elasticity in MFS mice as compared to vehicle treated groups. Our data indicate that systemic disruption of caveolae structure is detrimental, while specific targeting of Cav‐1 protein activity may be beneficial and protective in the context of MFS‐associated aortic aneurysm. This study provides insights into the role that caveolae may play during the progression of aortic aneurysm, and warrant further investigation into the potential value of Cav‐1 protein as a potential therapeutic target in MFS‐associated aortic aneurysm.Support or Funding InformationMarfan FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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