Abstract P295: Endothelial Sodium Channel Activation Promotes Cardiac Stiffness in Obese Female Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Javad Habibi ◽  
Annayya R Aroor ◽  
Lixin Ma ◽  
Guanghong Jia ◽  
Adam Whaley-Connell ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Low Dose ◽  
Interstitial Fibrosis ◽  
Diastolic Heart Failure ◽  
The United States ◽  
High Fat ◽  
Female Mice ◽  
Obese Female ◽  
High Fructose ◽  
Endothelial Stiffness

Cardiac diastolic dysfunction (DD) and diastolic heart failure is increasing in concert with obesity and aging population in the United States. In obese and diabetic women, DD is more common than in their male counterparts. This disproportionate increase in DD in obese females may partly explain their loss of sex-related cardiovascular (CV) disease protection. Recent studies have suggested a role for endothelial sodium channel (ENaC) activation in promotion of endothelial stiffness and suppression of flow- (nitric oxide) mediated vasodilation. Moreover, increased mineralocorticoid receptor (MR) activation mediated endothelial stiffness is promoted, in part, by ENaC activation. In this regard, we have recently reported increased plasma aldosterone levels, aortic and cardiac stiffness, and cardiac and vascular MR expression in female mice fed a high fat and high fructose diet (western diet [WD]). This increase in CV stiffness was prevented by very low dose MR antagonism. Accordingly, we hypothesized that inhibition of MR-mediated ENaC activation by using a very low dose of the ENaC inhibitor, amiloride would prevent cardiac stiffening (DD) in WD-fed female mice. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a very low dose of amiloride (1mg/kg/day) for 16 weeks. Amiloride significantly attenuated WD-induced impairment of cardiac relaxation in vivo as measured by high resolution magnetic resonance imaging (MRI) as well as cardiac interstitial fibrosis as measured by immunohistochemistry by picrosirius red staining. Moreover, amiloride prevented the development of DD in obese female mice without having effects on blood pressure. These observations support a role for ENaC activation in diet-induced cardiac stiffening (DD) in obese females.

Abstract P293: Endothelial Sodium Channel Activation Promotes Vascular Stiffness in Obese Female Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Annayya Aroor ◽  
Francisco I Ramirez-Perez ◽  
Guanghong Jia ◽  
Javad Habibi ◽  
Vincent G DeMarco ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Aortic Stiffness ◽  
Low Dose ◽  
Vascular Stiffness ◽  
Obese Women ◽  
High Fat ◽  
Arterial Stiffening ◽  
Female Mice ◽  
High Fructose ◽  
Endothelial Stiffness

Obesity-associated arterial stiffening is an independent predictor of cardiovascular disease (CVD) events. Although premenopausal non-obese women are protected against CVD, aortic stiffening in obese women is more common than in men. This disproportionate increase in vascular stiffness in obese females may partly explain their loss of sex-related CVD protection. Recent studies have suggested a role for endothelial sodium channel (ENaC) activation in promotion of endothelial stiffness and suppression of flow-(nitric oxide) mediated vasodilation. Increased mineralocorticoid receptor (MR) activation mediated endothelial stiffness is promoted, in part, by ENaC activation. In this regard, we have recently reported increased aortic stiffness, MR and ENaC expression and endothelial dysfunction in female mice fed a high fat and high fructose diet (western diet [WD]). This increase in aortic stiffness was prevented by very low dose MR antagonism. Accordingly, we hypothesized that inhibition of MR-mediated ENaC activation by using a very low dose of the ENaC inhibitor, amiloride, would prevent arterial stiffening and vascular dysfunction in WD-fed female mice. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a very low dose of amiloride (1mg/kg/day) for 16 weeks. Amiloride significantly attenuated WD-induced increases in aortic stiffness in vivo as measured by pulse wave velocity as well as in vitro endothelial stiffness as measured by atomic force microscopy. Moreover, incubation of aortic explants with very low dose of amiloride (1 μM) inhibited WD-induced aortic stiffness in aorta explants from WD-fed female mice. Amiloride also prevented WD-induced impairment in acetylcholine-induced aortic vasodilatation and flow-mediated dilation in mesenteric arteries. Taken together, these observations support a role for ENaC activation in diet-induced vascular stiffening in obese females.

scholarly journals Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

2020 ◽  
Author(s):  
Geronimo Matteo ◽  
Myriam P Hoyeck ◽  
Hannah L Blair ◽  
Julia Zebarth ◽  
Kayleigh RC Rick ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
Low Dose ◽  
Dependent Manner ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Insulin Levels ◽  
Plasma Insulin Levels

AbstractObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that acute high-dose TCDD exposure (20 μg/kg) decreased plasma insulin levels in both male and female mice in vivo; however, effects on glucose homeostasis were sex-dependent. The purpose of this study was to determine whether prolonged exposure to a physiologically relevant dose of TCDD impairs beta cell function and/or glucose homeostasis in a sex-dependent manner in either chow-fed or HFD-fed mice.MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks, and simultaneously fed a chow or 45% high-fat diet (HFD). Glucose metabolism was assessed by glucose and insulin tolerance tests throughout the study. Islets were isolated from females at 12 weeks for Tempo-Seq® analysis.ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. In addition, islet TempO-Seq® analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females.ConclusionsOur data suggest that TCDD exposure is more deleterious when combined with HFD-feeding in female mice, and that low-dose TCDD exposure increases diabetes susceptibility in females.

Enhanced endothelium epithelial sodium channel signaling prompts left ventricular diastolic dysfunction in obese female mice

Metabolism ◽  
2018 ◽  
Vol 78 ◽  
pp. 69-79 ◽  
Author(s):  
Guanghong Jia ◽  
Javad Habibi ◽  
Annayya R. Aroor ◽  
Michael A. Hill ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Female Mice ◽  
Obese Female ◽  
Ventricular Diastolic Dysfunction

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.

Mice on a high-fat, high-fructose diet and treated with low dose streptozotocin develop features of human NASH

2012 ◽  
Vol 50 (08) ◽  
Author(s):  
YO Kim ◽  
M Stoll ◽  
B Hebich ◽  
S Weng ◽  
X Wang ◽  
...  
Keyword(s):  
Low Dose ◽  
High Fat ◽  
High Fructose Diet ◽  
High Fructose

Low-dose pollutant mixture triggers metabolic disturbances in female mice leading to common and specific features as compared to a high-fat diet

2017 ◽  
Vol 45 ◽  
pp. 83-93 ◽  
Author(s):  
Emmanuel Labaronne ◽  
Claudie Pinteur ◽  
Nathalie Vega ◽  
Sandra Pesenti ◽  
Benoit Julien ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Low Dose ◽  
High Fat ◽  
Metabolic Disturbances ◽  
Female Mice

Effects of Irisin and Exercise on Metabolic Parameters and Reproductive Hormone Levels in High-Fat Diet-Induced Obese Female Mice

2017 ◽  
Vol 25 (2) ◽  
pp. 281-291 ◽  
Author(s):  
Ercan Bastu ◽  
Umit Zeybek ◽  
Ebru Gurel Gurevin ◽  
Bahar Yüksel Ozgor ◽  
Faruk Celik ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Metabolic Parameters ◽  
Reproductive Hormone ◽  
High Fat ◽  
Hormone Levels ◽  
Female Mice ◽  
Obese Female

scholarly journals Tu1815 Mice Fed a High-Fat High-Fructose Diet and Treated With Low Dose Streptozotocin Develop Insulin Resistance, NASH and Liver Fibrosis

2012 ◽  
Vol 142 (5) ◽  
pp. S-1024
Author(s):  
Yong Ook Kim ◽  
Matthias Stoll ◽  
Bernhard Hebich ◽  
Xiaoyu Wang ◽  
Detlef Schuppan
Keyword(s):  
Insulin Resistance ◽  
Liver Fibrosis ◽  
Low Dose ◽  
High Fat ◽  
High Fructose Diet ◽  
High Fructose
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