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 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 608: Uric Acid Potentially Interacts With Parathyroid Hormone To Promote Left Ventricular Diastolic Dysfunction In Mice Fed A Western Diet

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Guanghong Jia ◽  
Brian P Bostick ◽  
Javad Habibi ◽  
Annayya R. Aroor ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Uric Acid ◽  
Parathyroid Hormone ◽  
Diastolic Dysfunction ◽  
Cardiac Mri ◽  
Left Ventricular ◽  
Western Diet ◽  
P Value ◽  
Lv Diastolic Dysfunction

Hyperuricemia is frequently observed in obese people and rising obesity rates parallel increased consumption of a high-fat/high-fructose western diet (WD). Epidemiologic and clinical data suggest that serum uric acid (UA) is positively associated with serum parathyroid hormone (PTH) and may be linked with left ventricular (LV) hypertrophy and LV diastolic dysfunction. Accordingly, we hypothesized that allopurinol, a potent xanthine oxidase (XO) inhibitor, would prevent development of LV diastolic dysfunction, independent of blood pressure, by reducing the levels of UA and PTH. Four week-old C57BL6/J male mice were fed a WD and water with 125mg/L allopurinol. After 16 weeks, we assessed levels of UA, XO activity, PTH, as well as diastolic function by cardiac MRI and cardiac ultrastructure by transmission electron microscopy (TEM). Body weight and fat composition were obtained along with HOMA -IR testing for insulin resistance. Allopurinol has been show to exert no effect on blood pressure. High resolution cardiac MRI revealed diastolic dysfunction with WD feeding that was prevented by allopurinol (LV diastolic relaxation time 35.3 ms for WD, 25.4 ms for CD and 27.7 ms for WD+ allopurinol, p value <0.01; Initial filling rate 0. 28 μl/ms for WD, 0.43 μl/ms for CD and 0.42 μl/ms for WD+ allopurinol, p value <0.05). Body weight, fat mass, and HOMA-IR were increased by WD feeding but not significantly improved by allopurinol. However, allopurinol markedly decreased the WD-induced increase in heart weight associated with activation of translational S6 kinase. TEM examination of myocardial ultrastructure revealed that WD induced remodeling changes with large mitochondria with disordered cristae and increased lysosomes. The ultrastructural changes were improved with treatment by allopurinol. Furthermore, allopurinol significantly inhibited both of plasma and urine UA levels and cardiac XO activity caused by WD. Interestingly , WD increased PTH levels which were decreased in parallel with reductions in uric acid with allopurinol. These findings support the notion that increased plasma levels of UA, in concert with elevated PTH, may play a key role in LV hypertrophy and associated LV diastolic dysfunction that result from consuming a WD high in fructose and fat.

scholarly journals Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

Diabetes Care ◽  
2013 ◽  
Vol 36 (12) ◽  
pp. 4083-4090 ◽  
Author(s):  
H. Sell ◽  
M. Bluher ◽  
N. Kloting ◽  
R. Schlich ◽  
M. Willems ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4

scholarly journals Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Camila Manrique ◽  
Javad Habibi ◽  
Annayya R. Aroor ◽  
James R. Sowers ◽  
Guanghong Jia ◽  
...  
Keyword(s):  
Dipeptidyl Peptidase ◽  
Western Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Vascular Abnormalities ◽  
Female Mice

Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance

2016 ◽  
Vol 7 (1) ◽  
pp. 475-482 ◽  
Author(s):  
Chien-Ning Huang ◽  
Chau-Jong Wang ◽  
Yi-Sun Yang ◽  
Chih-Li Lin ◽  
Chiung-Huei Peng
Keyword(s):  
Insulin Resistance ◽  
Diabetic Nephropathy ◽  
Epithelial Mesenchymal Transition ◽  
Dipeptidyl Peptidase ◽  
Socioeconomic Impact ◽  
Hibiscus Sabdariffa ◽  
Mesenchymal Transition ◽  
Dipeptidyl Peptidase 4

Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined.

Abstract 555: The Effect Of Dipeptidyl Peptidase 4 Inhibition On Arterial Blood Pressure Is Context Dependent

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Edwin K Jackson ◽  
Zaichuan Mi ◽  
Stevan P Tofovic ◽  
Delbert G Gillespie
Keyword(s):  
Blood Pressure ◽  
Dipeptidyl Peptidase ◽  
Sprague Dawley ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
The Metabolic Syndrome ◽  
Arterial Blood ◽  
Blood Pressures ◽  
Context Dependent ◽  
Wistar Kyoto

Dipeptidyl peptidase 4 (DPP4) inhibitors decrease the metabolism of endogenous glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, such as GLP-1(7-36)NH 2 , and GLP-1R agonists are antihypertensive. However, DPP4 inhibitors also impair the metabolism of endogenous Y 1 receptor (Y 1 R) agonists, such as neuropeptide Y 1-36 (NPY 1-36 ), and Y 1 R agonists are pro-hypertensive. Consequently, the long-term effect of DPP4 inhibition on blood pressure may be context dependent. To test this, we conducted radiotelemetry studies under highly controlled conditions to quantify the effects of chronic sitagliptin (80 mg/kg/day; DPP4 inhibitor) on blood pressure in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and Zucker Diabetic-Sprague Dawley rats (ZDSD; model of the metabolic syndrome developed by PreClinOmics). In SHR, chronic (3 weeks) administration of sitagliptin significantly increased systolic, mean and diastolic blood pressures by 10.3, 9.2 and 7.9 mmHg, respectively (p<0.01). Sitagliptin also significantly (p<0.01) increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg/day) or enalapril (ACE inhibitor; 10 mg/kg/day). Co-administration of BIBP3226 (2 mg/kg/day; Y 1 R antagonist) abolished the pro-hypertensive effects of sitagliptin in SHR. In WKY, chronic sitagliptin slightly decreased (p<0.01) systolic, mean and diastolic blood pressures (-1.8, -1.1 and -0.4 mmHg, respectively). In ZDSD, chronic sitagliptin markedly decreased systolic, mean and diastolic blood pressures (-7.7, -5.8, -4.3 mmHg, respectively). In isolated, perfused ZDSD kidneys pretreated with norepinephrine to induce basal tone, NPY 1-36 and GLP-1(7-36)NH 2 exerted little effect on renovascular tone. In contrast, in isolated SHR kidneys, both NPY 1-36 and GLP-1(7-36)NH 2 elicited potent and efficacious vasoconstriction (increased perfusion pressure by 171 and 132 mmHg, respectively). Conclusions: 1) The effects of DPP4 inhibitors on blood pressure are context dependent; 2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to its most important substrates (NPY 1-36 and GLP-1(7-36)NH 2 ); 3) Y 1 R antagonists may augment the beneficial effects of DPP4 inhibitors.

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