Abstract P232: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, Linagliptin, Prevents Aortic Stiffening and Vascular and Cardiac Diastolic Dysfunction Caused by Western Diet Feeding in Female Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Vincent G DeMarco ◽  
Annayya Aroor ◽  
Guanghong Jia ◽  
Javad Habibi ◽  
Mona Garro ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Aortic Stiffness ◽  
Vascular Reactivity ◽  
Control Diet ◽  
Western Diet ◽  
Obese Women ◽  
Dipeptidyl Peptidase 4 ◽  
Force Microscopy ◽  
Aortic Stiffening ◽  
Endothelial Stiffness

Aortic stiffness, endothelial dysfunction and diastolic dysfunction (DD) are cardiovascular (CV) abnormalities seen in obesity associated with consumption of high fat/fructose western diet (WD). Moreover, CV dysfunction is increasingly prevalent in obese women. Herein, we examined whether the DPP-4 inhibitor, linagliptin (LINA), improves these outcomes in WD fed female C57BL/6 mice. Four week old mice were fed control diet (CD) or WD with or without LINA for 16 weeks, after which pulse wave velocity (aortic stiffness) (PWV), echocardiography (diastolic function), atomic force microscopy (endothelial stiffness) and wire myography (aortic vascular reactivity) were performed. Compared to CD mice, WD mice exhibited 21% and 353% higher PWV and endothelial stiffness, respectively. WD induced DD, indicated by impaired septal wall motion (<E’/A’ ratio), left atrial filling pressure (>E/Vp ratio), prolonged isovolumic relaxation time (IVRT) and impaired myocardial performance index (>MPI). These vascular and cardiac abnormalities were prevented by LINA. LINA also prevented WD-induced impairments in acetylcholine-, sodium nitroprusside-, and insulin-mediated aortic vascular relaxation. These results show that LINA exerts CV protection in a translational model of obesity.

Abstract 655: Dipeptidyl Peptidase-4 (dpp-4) Inhibition Decreases Cardiac And Vascular Stiffness And Improves Cardiac And Vascular Relaxation In Western Diet Fed Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Annayya R Aroor ◽  
Vincent G DeMarco ◽  
Guanghong Jia ◽  
Luis A Martinez-Lemus ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Endothelial Cell ◽  
Diastolic Dysfunction ◽  
Dipeptidyl Peptidase ◽  
Western Diet ◽  
Vascular Relaxation ◽  
S6 Kinase ◽  
Dipeptidyl Peptidase 4 ◽  
Endothelial Stiffness

A western diet (WD), high in sucrose and fat, is often accompanied by insulin resistance and cardiovascular disease characterized early by endothelial dysfunction and increased vascular and cardiac stiffness. Recently, Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to improve diastolic dysfunction in WD fed mice, but its effects on endothelial cell and cardiac stiffness have not been reported. We fed 4-week old C57BL/6 male mice with a WD with or without a DPP-4 inhibitor (MK0626) for 16 weeks and measured blood pressure by telemetry, insulin resistance via (HOMA), in vivo cardiac diastolic function (echocardiography), pulse wave velocity (PWV), and ex vivo aortic endothelial stiffness by atomic force microscopy. Systolic blood pressure and insulin resistance were increased by the WD. DPP-4 inhibition improved systemic insulin sensitivity and substantially reduced DPP-4 activity, but had no effect on 24-hour blood pressures. Heart weight was increased by WD in conjunction with S6 kinase translational signaling and DPP-4 inhibition reduced S6 kinase phosphorylation/activation in conjunction with a reduction in cardiac mass. Aortic stiffness, as assessed by PWV, was significantly increased in WD fed mice (16% increase) and was markedly decreased by DPP-4 inhibition. Endothelial cell stiffness was increased 5-fold in WD fed mice and DPP-4 inhibition significantly decreased endothelial stiffness (80% decrease). Acetylcholine but not sodium nitroprusside mediated vascular relaxation was impaired in WD fed mice and DPP-4 inhibition significantly improved this nitric oxide mediated relaxation. Increased vascular smooth muscle and endothelial stiffness was associated with impaired cardiac diastolic relaxation, which was also significantly improved by DPP-4 inhibition. Taken together, these results show that DPP-4 inhibition improves cardiac and vascular endothelial stiffness and cardiac diastolic dysfunction in a clinically translational mouse model (WD) of over nutrition and insulin resistance.

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 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.

2357-PUB: Dapagliflozin for 52 Weeks Improves Diastolic Dysfunction and Vascular Reactivity in T2D

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 2357-PUB
Author(s):  
ILENIA D'IPPOLITO ◽  
ELISA DE CARLI ◽  
AIKATERINI ANDREADI ◽  
MARIA ROMANO ◽  
ANGELICA GALLI ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Vascular Reactivity

scholarly journals Rapid ascending aorta stiffening in bicuspid aortic valve on serial cardiovascular magnetic resonance evaluation: comparison with connective tissue disorders

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Alejandro Perez-Casares ◽  
Audrey Dionne ◽  
Kimberlee Gauvreau ◽  
Ashwin Prakash
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Magnetic Resonance ◽  
Aortic Valve ◽  
Connective Tissue ◽  
Bicuspid Aortic Valve ◽  
Aortic Stiffness ◽  
Comparison Group ◽  
Aortic Distensibility ◽  
Connective Tissue Disorders ◽  
Aortic Stiffening

Abstract Background Aortic stiffness has been shown to be abnormal in patients with bicuspid aortic valve (BAV), and is considered a component of the aortopathy associated with this condition. Progressive aortic stiffening associated with aging has been previously described in normal adults. However, it is not known if aging related aortic stiffening occurs at the same rate in BAV patients. We determined the longitudinal rate of decline in segmental distensibility in BAV patients using serial cardiovascular magnetic resonance (CMR) studies, and compared to previously published results from a group of patients with connective tissue disorders (CTD). Methods A retrospective review of CMR and clinical data on children and adults with BAV (n = 49, 73% male; 23 ± 11 years) with at least two CMRs (total 98 examinations) over a median follow-up of 4.1 years (range 1–9 years) was performed to measure aortic distensibility at the ascending (AAo) and descending aorta (DAo). Longitudinal changes in aortic stiffness were assessed using linear mixed-effects modeling. The comparison group of CTD patients had a similar age and gender profile (n = 50, 64% male; 20.6 ± 12 years). Results Compared to CTD patients, BAV patients had a more distensible AAo early in life but showed a steeper decline in distensibility on serial examinations [mean 10-year decline in AAo distensibility (× 10−3 mmHg−1) 2.4 in BAV vs 1.3 in CTD, p = 0.005]. In contrast, the DAo was more distensible in BAV patients throughout the age spectrum, and DAo distensibility declined with aging at a rate similar to CTD patients [mean 10 year decline in DAo distensibility (× 10−3 mmHg−1) 0.3 in BAV vs 0.4 in CTD, p = 0.58]. Conclusions On serial CMR measurements, AAo distensibility declined at significantly steeper rate in BAV patients compared to a comparison group with CTDs, while DAo distensibility declined at similar rates in both groups. These findings offer new mechanistic insights into the differing pathogenesis of the aortopathy seen in BAV and CTD patients.

scholarly journals Exercise prevents Western diet-associated erectile dysfunction and coronary artery endothelial dysfunction: response to acute apocynin and sepiapterin treatment

2013 ◽  
Vol 305 (4) ◽  
pp. R423-R434 ◽  
Author(s):  
Justin D. La Favor ◽  
Ethan J. Anderson ◽  
Jillian T. Dawkins ◽  
Robert C. Hickner ◽  
Christopher J. Wingard
Keyword(s):  
Erectile Dysfunction ◽  
Coronary Artery ◽  
Exercise Training ◽  
Erectile Function ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
Control Diet ◽  
Western Diet ◽  
Treadmill Running ◽  
Aerobic Exercise Training

The aim of this study was to investigate aerobic exercise training as a means to prevent erectile dysfunction (ED) and coronary artery disease (CAD) development associated with inactivity and diet-induced obesity. Male Sprague-Dawley rats were fed a Western diet (WD) or a control diet (CD) for 12 wk. Subgroups within each diet remained sedentary (Sed) or participated in aerobic interval treadmill running throughout the dietary intervention. Erectile function was evaluated under anesthesia by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, in the absence or presence of either apocynin, an NADPH oxidase inhibitor, or sepiapterin, a tetrahydrobiopterin precursor. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of ACh applied to preconstricted segments of the left anterior descending coronary artery. CAEF was assessed in the absence or presence of apocynin or sepiapterin. Erectile function ( P < 0.0001) and CAEF ( P < 0.001) were attenuated in WD-Sed. Exercise preserved erectile function ( P < 0.0001) and CAEF ( P < 0.05) within the WD. Erectile function ( P < 0.01) and CAEF ( P < 0.05) were augmented by apocynin only in WD-Sed, while sepiapterin ( P < 0.05) only augmented erectile function in WD-Sed. These data demonstrate that a chronic WD induces impairment in erectile function and CAEF that are commonly partially reversible by apocynin, whereas sepiapterin treatment exerted differential functional effects between the two vascular beds. Furthermore, exercise training may be a practical means of preventing diet-induced ED and CAD development.

Abstract 336: Rats with Adenine-Induced Chronic Renal Failure Develop Low-Renin Hypertension That is Aggravated by High NaCl Diet and Associated with Increased Aortic Stiffness

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Gregor Guron ◽  
Lisa Nguy ◽  
Maria Johansson ◽  
Tom Teerlink
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Aortic Stiffness ◽  
Control Diet ◽  
Plasma Renin ◽  
Aortic Pulse Wave Velocity ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Pronounced Increase ◽  
Low Renin Hypertension

We have shown that rats with adenine-induced chronic renal failure (A-CRF) develop modest hypertension, left ventricular hypertrophy, and a marked decrease in aortic relaxation rate. The aim of this study was to investigate mechanisms causing hypertension in this model and to assess aortic stiffness by measuring aortic pulse wave velocity (PWV). Male Sprague-Dawley rats were equipped with radiotelemetry probes and subsequently received either chow containing adenine (0.5% for 3 weeks, 0.3% for 2 w., and 0.15% thereafter) or were pair-fed with a normal control diet. At 7 to 11 weeks blood pressure responses to high NaCl diet (4%) and pharmacological interventions were performed. In separate groups aortic PWV was analyzed in isoflurane-anesthetized animals. Values are means±SD. Baseline 24-h mean arterial pressure (MAP) was 101±10 and 119±9 mmHg in controls and A-CRF animals, respectively (P < 0.01). After 5 days of 4% NaCl diet MAP had increased by 24±6 mmHg in A-CRF animals vs. 2±1 mmHg in controls (P<0.001 between groups). Administration of L-NAME in the drinking water (50 mg/kg/day) increased MAP by 37±9 and 24±4 mmHg in A-CRF animals and controls, respectively (P< 0.01 between groups). Candesartan (10 mg/kg by gavage) produced a more pronounced reduction of MAP in controls vs. A-CRF animals (-12±3 vs. -5±5 mmHg, P<0.05). Aortic PWV was elevated in A-CRF rats (5.10±0.51 vs. 4.58±0.17 m/s, P<0.05) although histological analysis did not show aortic calcifications. At sacrifice, plasma levels of creatinine (259±46 vs. 31±2 μM, P<0.001) and asymmetric dimethylarginine (ADMA, 0.65±0.04 vs. 0.45±0.02 μM, P < 0.001) were elevated in A-CRF animals whereas plasma renin activity was markedly suppressed (0.7±0.5 vs. 15.1±7.5 μg/L/h, P<0.001). Hypertension in A-CRF animals is characterized by low renin levels and is aggravated by high NaCl diet suggesting a pathogenic role for hypervolemia secondary to severe renal insufficiency. Although ADMA concentrations were elevated, A-CRF animals showed a more pronounced increase in MAP in response to L-NAME than controls, suggesting that reduced nitric oxide synthase activity was not a major cause of hypertension in this model. Finally, aortic stiffness was elevated in A-CRF animals as indicated by increased aortic PWV.

Abstract P231: Inhibition of Mir-762 Prevents and Reverses Ang II Induced Aortic Stiffening

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Aortic Stiffness ◽  
Fold Increase ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

Abstract 616: MicroRNA miR-29b is a Mediator of Aortic Stiffness and Hypertension in a Murine Model of Type 2 Diabetes Mellitus

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Uwe Raaz ◽  
Isabel N Schellinger ◽  
Lars Maegdefessel ◽  
Joshua M Spin ◽  
Gerd Hasenfuss ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pulse Pressure ◽  
Aortic Stiffness ◽  
Target Genes ◽  
Ex Vivo ◽  
Matrix Remodeling ◽  
Collagen Deposition ◽  
Arterial Stiffening ◽  
Vascular Stiffening ◽  
Aortic Stiffening

Background: Accelerated arterial stiffening is a complication of diabetes mellitus and associated with the development of hypertension. Arterial stiffening results from extensive extracellular matrix remodeling (elastin breakdown, collagen accumulation). MicroRNA miR-29b directly regulates the expression of genes governing fibrosis (such as COL1A1, COL3A1) and elastin breakdown ( MMP2, MMP9 ). However, its impact on aortic stiffness is unclear. Objective: This study was designed to investigate the role of miR-29b as potential mediator of diabetic aortic stiffening. Methods and Results: Serial ex vivo mechanical testing of the thoracic aorta and volume-pressure recording (VPR) based tail-cuff blood pressure measurements revealed that aortic stiffening precedes blood (pulse) pressure elevations in diabetic db/db mice. Vascular stiffening was accompanied by increased elastin fragmentation and collagen deposition (EvG and Picrosirius Red staining). qRT-PCR, in-situ hybridization and immunohistochemistry revealed decreased expression of miR-29b and de-repression of target genes ( Col1A1, COL3A1, MMP2, MMP9 ) in db/db mice compared to controls. Investigating the mechanistic significance of miR-29b for arterial stiffening, forced downregulation of miR-29b (via systemic LNA-miR-29b inhibitor application) results in enhanced elastin fragmentation, increased medial collagen deposition, aortic stiffness and augmented pulse pressure. Conclusions: In conclusion this study identifies miR-29b as a regulator and potential therapeutic target of diabetic aortic stiffening.

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