scholarly journals Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

2017 ◽  
Vol 8 ◽  
Author(s):  
Luis A. Martinez-Lemus ◽  
Annayya R. Aroor ◽  
Francisco I. Ramirez-Perez ◽  
Guanghong Jia ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Female Mice

Cystamine reduces vascular stiffness in Western diet-fed female mice

2021 ◽  
Author(s):  
Francisco I. Ramirez-Perez ◽  
Francisco J. Cabral-Amador ◽  
Adam T. Whaley-Connell ◽  
Annayya R Aroor ◽  
Mariana Morales-Quinones ◽  
...  
Keyword(s):  
Tissue Transglutaminase ◽  
Vascular Wall ◽  
Aortic Pulse Wave Velocity ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Mesenteric Arteries ◽  
Chow Diet ◽  
Obese Women ◽  
Arterial Stiffening ◽  
Female Mice

Consumption of diets high in fat, sugar and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Obese women are more prone to develop arterial stiffening leading to more frequent and severe CVD compared to men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a non-specific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 weeks starting at four weeks of age. The second was fed a WD for the same 43 weeks, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/d) in the drinking water during the last eight weeks on the diet (WD+C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- vs. CD-fed mice, and reduced in WD+C vs. WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin/G-actin ratio, collagen compaction capacity and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely due to its TG2 inhibitory capacity.

Abstract P068: Endothelial Mineralocorticoid Receptor Activation Promotes Endothelial And Vascular Stiffening In Western Diet Fed Female Mice Through Sgk1 Mediated Activation Of The Endothelial Sodium Channel

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Yan Yang ◽  
Zhe Sun ◽  
Annayya Aroor ◽  
Liping Zhang ◽  
Guanghong Jia ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Mineralocorticoid Receptor ◽  
Sodium Current ◽  
Receptor Activation ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Female Mice ◽  
Isolated Lung ◽  
Vascular Stiffening ◽  
Endothelial Stiffness

Over-nutrition/obesity predisposes persons, particularly women, to endothelial dysfunction and vascular stiffening. We have employed a clinically relevant model using female mice fed a high fat and high fructose diet (western diet, WD). These mice display high plasma aldosterone levels, endothelial stiffness and dysfunction and increased mineralocorticoid receptor (MR) expression in the vasculature. One potential mechanism by which MR activation may promote endothelial stiffness is through increased expression and activation of epithelial sodium channel (EnNaC) in endothelial cells (ECs) through mTOR2 mediated activation of serum and glucocorticoid regulated kinase 1(SGK1). In this investigation we observed that WD feeding in female mice for 16 wks caused endothelial (atomic force microscopy (AFM)), and aortic stiffening (PW analysis) in concert with increased expression of EnNaC and SGK1 in the endothelium and EnNaC activation in ECs. Further, amelioration of WD induced EC and vascular stiffness was accomplished by EnNaC inhibition with low dose amiloride (1mg/kg/day in drinking water) over the 16 wks of WD. We then explored the idea that inhibition of SGK1 as well as specific deletion of ECMR and EnNaC decreases vascular EC stiffness accompanied by decreased sodium current in isolated lung ECs. Accordingly, female wild type and ECMR and EnNaC KO mice were fed a WD or control diet (CD) for 16 wks. Aortic and coronary artery EC stiffness, measured ex vivo by AFM, was increased in WD fed mice and this was prevented in ECMR and EnNaC KO models. Both ECMR and EnNaC KO mice fed a WD showed decreased amiloride sensitive sodium current in isolated ECs. Further, in cultured ECs , inhibition of SGK1 by a chemical inhibitor attenuated aldosterone mediated sodium currents. Collectively, these findings support the notion that a WD promotes ECMR mediated increases in SGK1 and associated EnNaC activity in ECs together with increased endothelial and vascular stiffness in females.

scholarly journals Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1590-1600 ◽  
Author(s):  
Camila Manrique ◽  
Guido Lastra ◽  
Francisco I. Ramirez-Perez ◽  
Dominic Haertling ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Vascular Reactivity ◽  
Control Diet ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Vascular Stiffening

Abstract Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

scholarly journals Myeloid deletion and therapeutic activation of AMP-activated protein kinase (AMPK) do not alter atherosclerosis in male or female mice

2020 ◽  
Author(s):  
Nicholas D. LeBlond ◽  
Peyman Ghorbani ◽  
Conor O’Dwyer ◽  
Nia Ambursley ◽  
Julia R. C. Nunes ◽  
...  
Keyword(s):  
Protein Kinase ◽  
First Generation ◽  
Western Diet ◽  
Daily Injection ◽  
Catalytic Subunits ◽  
Male And Female ◽  
Ampk Signaling ◽  
Female Mice ◽  
Amp Activated Protein Kinase ◽  
Progression Of Atherosclerosis

AbstractObjectiveThe dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis.Approach and ResultsWe aimed to clarify the role of myeloid-specific AMPK signaling by using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), in male and female mice made acutely atherosclerotic by PCSK9-AAV and Western diet-feeding. After 6 weeks of Western diet feeding, half received daily injection of either the AMPK activator, A-769662 or a vehicle control for a further 6 weeks. After 12 weeks, myeloid cell populations were not different between genotype or sex. Similarly, aortic sinus plaque size, lipid staining and necrotic area were not different in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 had no effect. There were no differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area or markers of autophagy showed no effect of either lacking AMPK signaling or systemic AMPK activation.ConclusionsOur data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Moreover, we show that intervention with the first-generation AMPK activator, A-769662, was not able to stem the progression of atherosclerosis.Highlights- The deletion of both catalytic subunits of AMPK in myeloid cells has no significant effect on the progression of atherosclerosis in either male or female mice- Therapeutic delivery of a first-generation AMPK activator (A-769662) for the last 6 weeks of 12-week study had no beneficial effect in either male or female mice- Studying total AMPK deletion may mask specific effects of each isoform and highlights the need for targeted disruption of AMPK phosphorylation sites via knock-in mutations, rather than the traditional “sledgehammer” knockout approach

scholarly journals Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats

2009 ◽  
Vol 107 (4) ◽  
pp. 1249-1257 ◽  
Author(s):  
Jae Hyung Kim ◽  
Lukasz J. Bugaj ◽  
Young Jun Oh ◽  
Trinity J. Bivalacqua ◽  
Sungwoo Ryoo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Stiffness ◽  
Arginase Activity ◽  
Young Rats ◽  
Arginase 1 ◽  
Enos Uncoupling ◽  
Old Rats

There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2−) production than young. Acute inhibition of both NOS, with NG-nitro-l-arginine methyl ester, and arginase, with 2( S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O2− production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O2− production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

2021 ◽  
Author(s):  
Jazmin A Cole ◽  
Mackenzie N Kehmeier ◽  
Bradley R Bedell ◽  
Sahana Krishna Kumaran ◽  
Grant D Henson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Frailty Index ◽  
Mesenteric Arteries ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

Abstract 832: The Farnesoid X Receptor (FXR) Antagonizes Oxidized LDL Receptor, LOX-1, Activation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Douglas Harnish ◽  
Ashleigh Hahn ◽  
Helen Hartman ◽  
Christine Huard ◽  
Robert Martinez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Nuclear Hormone Receptor ◽  
Western Diet ◽  
Farnesoid X Receptor ◽  
Chow Diet

The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of enterohepatic circulation and lipid homeostasis and may also positively impact vascular inflammation and endothelial function through the antagonism of oxidized LDL receptor, LOX-1, activation. LOX-1 is a endothelial membrane bound scavenger receptor that upon ligand binding stimulates NF-κB and MAPK pathways leading to adhesion molecule and inflammatory gene expression with subsequent nitric oxide inhibition. Since LOX-1 is activated by oxLDL, LOX-1 expression was monitored in LDLR −/− mice fed a western diet. Hepatic LOX-1 mRNA was significantly induced by 7 days on the western diet compared to chow fed controls. Moreover, this LOX-1 induction was dose dependently inhibited with increasing concentrations of a potent synthetic FXR ligand WAY-362450 (FXR-450; 1–30 mg/kg po) as were downstream LOX-1 dependent genes, VCAM-1 and ICAM-1. The regulation of LOX-1 was FXR-specific since another oxLDL hepatic scavenger receptor, CD36, expression was not affected by FXR-450. To determine whether this signaling pathway was active in other settings, the FXR mediated regulation of LOX-1 was studied in the diabetic mouse strain, KKAy. Both hepatic and renal LOX-1 expression was inhibited by 30 mg/kg FXR-450 after 7 days of dosing on a chow diet and resulted in the reduction of serum soluble LOX-1 levels as well. Renal gene profiling studies indicated that FXR-450 stimulated genes involved in nitric oxide production, including DDAH-1, ASS-1 and GTPCH that were all confirmed to be induced in the KKAy mouse model. Since the nitric oxide synthase antagonist ADMA stimulates LOX-1 expression, we postulated that the positive impact of FXR-450 was due to the decrease in local ADMA concentrations via DDAH-1, ASS-1 and GTPCH inductions. In support of this, ADMA mediated induction of LOX-1 was also inhibited by FXR-450 treatment. Therefore, these results identify a novel cross-talk between FXR and LOX-1 signaling pathways through their co-ordinate modulation of the nitric oxide pathway and suggest that FXR agonists may have a beneficial impact on vascular inflammation and endothelial function.

scholarly journals The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Saivageethi Nuthikattu ◽  
Dragan Milenkovic ◽  
John Rutledge ◽  
Amparo Villablanca
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Differential Expression ◽  
Differential Gene Expression ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Western Diet ◽  
Protein Coding ◽  
Female Mice ◽  
Differential Gene

AbstractHyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

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