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ALTAN, VECDİ MELİH

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VECDİ MELİH

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ALTAN

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    Publication
    Role of the beta(3)-adrenergic receptor subtype in catecholamine-induced myocardial remodeling
    (2018-09-01) Mutlu, Gizem Kayki; Inan, Ebru Arioglu; Karaomerlioglu, Irem; Altan, VECDİ MELİH; YERSAL, NİLGÜN; KORKUSUZ, PETEK; Rocchetti, Marcella; Zaza, Antonio; ALTAN, VECDİ MELİH
    beta(3)-Adrenoceptors (AR) stimulate cardiac Na+/K+ pump in healthy hearts. beta(3)-ARs are upregulated by persistent sympathetic hyperactivity; however, their effect on Na+/K+ ATPase activity and ventricular function in this condition is still unknown. Here, we investigate preventive effects of additional beta(3)-AR activation (BRL) on Na+/K+ ATPase activity and in vivo hemodynamics in a model of noradrenaline-induced hypertrophy. Rats received NA or NA plus simultaneously administered BRL in vivo infusion for 14 days; their cardiac function was investigated by left ventricular pressure-volume analysis. Moreover, fibrosis and apoptosis were also assessed histologically. NA induced an hypertrophic pattern, as detected by morphological, histological, and biochemical markers. Additional BRL exposure reversed the hypertrophic pattern and restored Na+/K+ ATPase activity. NA treatment increased systolic function and depressed diastolic function (slowed relaxation). Additional BRL treatment reversed most NA-induced hemodynamic changes. NA decreased Na+/K+ pump alpha 2 subunit expression selectively, a change also reversed by additional BRL treatment. Increasing beta(3)-AR stimulation may prevent the consequences of chronic NA exposure on Na+/K+ pump and in vivo hemodynamics. beta(3)-AR agonism may thus represent a new therapeutic strategy for pharmacological modulation of hypertrophy under conditions of chronically enhanced sympathetic activity.
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    beta(3)-Adrenoceptor-mediated responses in diabetic rat heart
    (2014-01-01T00:00:00Z) Kayki-Mutlu, Gizem; Arioglu-Inan, Ebru; Ozakca, Isil; Ozcelikay, Arif T.; Altan, VECDİ MELİH; ALTAN, VECDİ MELİH
    beta 3-adrenoceptors mediate negative inotropic effect in contrast to classical beta(1)- and beta(2)-adrenoceptors. Cardiac (beta(3)-adrenoceptors are upregulated in experimental diabetes. Thus, cardiodepressant effect mediated by beta(3)-adrenoceptors has been proposed to contribute to the impaired cardiac function in this pathology. In our study, we investigated the influence of streptozotocindiabetes on cardiac contractility to beta(3)-adrenoceptors stimulation by using Langendorff-perfused rat hearts. BRL 37344, a selective (beta(3)-adrenoceptor agonist, induced dose-dependent decreases in left ventricular developed pressure (LVDP) in hearts from control rats. BRL 37344 also dose-dependently decreased +dP/dt and -dP/dt values. Effects of BRL 37344 were abolished by SR 59230, but not altered by nadolol pre-treatment. On the other hand, these effects of BRL 37344 were all significantly increased in hearts from diabetic rats. We also observed that diabetes significantly increased the mRNA levels encoding cardiac beta(3)-adrenoceptors. In addition, Gi(alpha 2) mRNA expressions were found to be increased in the cardiac tissue of diabetic rats as well. The effect of BRL 37344 on cardiac contractility was normalized upon treatment of diabetic rats with insulin. These data demonstrate an increased effect of beta(3)-adrenoceptor stimulation on hemodynamic function of the heart in accordance with an increased mRNA levels encoding cardiac beta(3)-adrenoceptors in 8-week diabetic rats.
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    Altered Heart Function In HighSucrose-fed Overweight Rats: In Vivo And In Vitro Investigations
    (2017-06-22) ARIOĞLU İNAN, EBRU; Toy Durak, Aysegul; Olgar, Yusuf; Tuncay, Erkan; KAYKI MUTLU, GİZEM; KARAÖMERLİOĞLU, İREM; ALTAN, VECDİ MELİH; TURAN, BELMA; ALTAN, VECDİ MELİH
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    The effect of dapagliflozin treatment on cardiac parameters in high fat fed and low dose STZ induced diabetic rat
    (2019-08-01T00:00:00Z) Karaomerlioglu, I.; Erdogan, B. R.; Mutlu, G. Kayki; Yesilyurt, Z. E.; Muderrisoglu, E.; Ozturk, N.; ALTAN, VECDİ MELİH; Inan, E. Arioglu; ALTAN, VECDİ MELİH
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    Publication
    Effects of sitagliptin on ß-adrenoceptor mediated relaxation in streptozotocin-diabetic rat aorta
    (2020-11-13T00:00:00Z) Muderrisoglu, Ayhanim Elif; Erdogan, Betul Rabia; Yeşilyurt, Zeynep Elif; Uyar Boztas, Ceren; Karacomerlioglu, İrem; Altan, Vecdi Melih; Arioglu İnan, Ebru; ALTAN, VECDİ MELİH
    Background/aim: Dipeptidyl peptidase-4 (DPP4) inhibitors, a class of oral antidiabetic drugs, have been shown to be protective on the vascular system because of their antiinflammatory, antiatherosclerotic, and vasodilatory effects. ß2-adrenoceptors (ß2-ARs) mediate the vasorelaxation in the aorta. However, ß3-adrenoceptor-mediated relaxation has not been studied in diabetic aorta yet. Thus, we aimed to study the effect of sitagliptin treatment on ß2- and ß3-adrenoceptor-mediated relaxations in the diabetic rat aorta. Materials and methods: Eight-week old Sprague Dawley rats were divided into three groups: control, diabetic, sitagliptin treated diabetic. Diabetes was induced by injection of streptozotocin (35 or 40 mg/kg, intraperitoneally). After 10 weeks of diabetes, some of the diabetic rats were treated with sitagliptin (orally, 10mg/kg/day). ß2- and ß3-AR-mediated relaxation responses were evaluated by using isoprenaline and CL 316,243, respectively. ß3-AR-mediated relaxation experiments were repeated in presence of L-NAME. Western blotting and immunohistochemistry were performed to determine the abundance of ß3-adrenoceptor and endothelial nitric oxide synthase (eNOS). Results: The isoprenaline-mediated relaxation response was impaired in the diabetic group and sitagliptin treatment did not improve it. There was no significant change in CL316,243 mediated-relaxation or protein expression of ß3-ARs among the groups. However, the ratio of phosphorylated eNOS/NOS protein was increased markedly in the sitagliptin treated group, which points the stimulating effect of this drug towards the eNOS pathway. Conclusion: Our results indicate that sitagliptin treatment does not alter ß-AR-mediated relaxation in streptozotocin-diabetic rat aorta; however, it significantly stimulates the eNOS pathway. Future studies are needed to clarify the relationship between the eNOS pathway and DPP-4 inhibition.
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    The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta(3)-adrenoceptors
    (2010-02-01T00:00:00Z) Arioglu, E.; Guner, S.; Ozakca, I.; Altan, VECDİ MELİH; Ozcelikay, A. T.; ALTAN, VECDİ MELİH
    Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gi alpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gi alpha(2), Gi alpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.
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    Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses
    (2017-08-01T00:00:00Z) Balcilar, Cennet; Ozakca, Isil; Altan, VECDİ MELİH; ALTAN, VECDİ MELİH
    Vascular tonus is controlled by endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF) and endotheliumderived contracting factor (EDCF) under physiological circumstances. In pathological conditions, impairment of endothelium-derived relaxation can be caused by both decrease in EDRF release and increase in EDCF release. The increase in EDCF is observed with diseases such as hypertension and diabetes. The contribution of Rho-kinase and activated protein kinase (AMPK), which have opposite effects, to the increased EDCF responses was investigated. Rho-kinases are the effectors of Rho which is one of the small guanosine triphosphate-binding proteins. They increase cytosolic Ca+2 concentration and cause vascular smooth muscle to contract, keeping myosin light chain (MLC) in phosphorylated state by affecting myosin phosphatase target subunit which dephosphorylates the MLC. The activities of Rho-kinases increase with the increase of EDCF function. AMPK is the energy sensor of the cell. It provides a vasculoprotective effect by causing endothelium-dependent and endothelium-independent relaxation in smooth muscle. In contrast to Rho-kinase pathway activity, AMPK pathway activity decreases with diseases in which the EDCF function increases. In cases such as diabetes and hypertension that endothelial function impairs toward vasocontraction, it is considered that evaluating Rho-kinase and AMPK pathways which mediate contraction and relaxation in vascular smooth muscle respectively, would provide clues on choosing therapeutic target for pathologies in which endothelial dysfunction is observed.
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    Nebivolol prevents desensitization of beta-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond beta(1)-adrenoceptor blockage
    (2013-05-01T00:00:00Z) Ozakca, Isil; Arioglu-Inan, Ebru; ESFAHANI, Hrag; Altan, VECDİ MELİH; BALLIGAND, Jean-Luc; Kayki-Mutlu, Gizem; Ozcelikay, A. Tanju; ALTAN, VECDİ MELİH
    The importance of chronic stimulation of beta-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of beta-blockers in the treatment of heart failure. Nebivolol is a third-generation beta-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or beta(3)-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on beta-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective beta(1)-adrenoceptor blocker. Rats infused by isoprenaline (100 mu g.kg(-1).day(-1), 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg.kg(-1).day(-1)), nebivolol (10 mg.kg(-1).day(-1)), or placebo for 13 days starting on day 1 after implantation of minipump. Both metoprolol and nebivolol caused a similar reduction on heart rate. Nebivolol mediated a significant improvement on cardiac mass, coronary flow, mRNA expression levels of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and atrial natriuretic peptide and phospholamban (PLN)/SERCA2a and phospho-PLN/PLN ratio compared with metoprolol and placebo. Nebivolol prevented the detrimental effects of isoprenaline infusion on isoprenaline (68% of control at 30 mu M), BRL37344 (63% of control at 0.1 mu M), and forskolin (64% of control at 1 mu M) responses compared with metoprolol (isoprenaline, 34% of control; BRL37344, no response; forskolin, 26% of control) and placebo (isoprenaline, 33% of control; BRL37344, 28% of control; forskolin, 12% of control). Both beta-blockers improved the changes in mRNA expressions of beta(1)- and beta(3)-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of beta-adrenoceptor signaling and the development of cardiac hypertrophy independent of its beta(1)-adrenoceptor blocking effect.
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    Beta-3 adrenoceptors: A potential therapeutic target for heart disease.
    (2019-06-18) KAYKI-MUTLU, G; KARAOMERLIOGLU, I; ARIOGLU-INAN, E; Altan, VECDİ MELİH; ALTAN, VECDİ MELİH