18 research outputs found
Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.
No full textThe recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte
Values and Preferences of Physicians and Patients With Nonvalvular Atrial Fibrillation Who Receive Oral Anticoagulation Therapy for Stroke Prevention
No full textAbstractBackgroundReal-world data on patients' and physicians' values related to the use of oral anticoagulant (OAC) therapy for stroke prevention in patients with nonvalvular atrial fibrillation are currently lacking. We sought to assess the values, preferences, and experience of patients who receive OAC therapy, and of physicians who prescribe OAC therapy.MethodsA national survey of randomly selected patients (n = 266) and physicians (n = 178) was conducted between May and September 2014. Each was asked to evaluate the importance of individual OAC attributes and identify which of 2 medication profiles they would prefer (individual attributes were progressively modified to determine which were the most valued and/or influenced treatment choice). Medication adherence and prescription practice was also assessed.ResultsThe preferences of patients and physicians regarding OAC therapy differed but largely focused on characteristics related to safety and, to a lesser extent, efficacy. When based solely on the basis of the attribute profile (blinded to the specific agent), physicians were more likely to select apixaban (61%), whereas patients showed no significant preference among apixaban, rivaroxaban, and warfarin. Despite this, 49% of physicians spontaneously stated rivaroxaban as their preferred agent (vs 25% apixaban). Patients prescribed and taking once daily medications (rivaroxaban or warfarin) showed better compliance with their OAC therapy (approximately 30% of twice daily medications being taken once daily, with significantly more missed doses compared with once daily medications).ConclusionsReal-world prescriptions do not reflect reported values, which suggests that other factors influence patient-physician decision-making around OAC therapy. Data on self-reported adherence to OAC therapy and discordance in the use of OACs from prescribed regimens are concerning and warrant further investigation
TCT-487 Door-to-Balloon Time as a Function of Mode of Referral: Results from the Ontario Provincial Cardiac Care Network Database
No full textHypertrophic responses to either endothelin-1 (ET-1) or angiotensin II (Ang II) in the absence (−siFTO) or presence (+siFTO) of FTO downregulation.
No full text<p>Hypertrophy was assessed by determining cell surface area as well as expression of ANP or β-MHC. Bottom two panels show Western blot data with representative blots for different treatments. N = 5. Ctl, control. No differences were observed between any treatment group.</p
Identification of FTO in cardiomyocytes and cardiac tissue and evidence for its upregulation by leptin.
No full text<p>Panel A shows FTO gene expression in cultured rat ventricular myocytes under control conditions (Ctl) and its stimulation by leptin (L) and lack of effect in the presence of the leptin receptor receptor antagonist SHLA (A). Panels B and C show Western blots and their quantitative analyses with identical treatments as shown in panel A. These panels also show suppression of FTO in myocytes transfected with FTO siRNA. Panels D and E demonstrate Western blots and their quantitative assessment of whole hearts from control animals or animals fed a high fat diet (H) for 12 weeks. The results also show suppression of cardiac FTO protein expression in animals treated with an antibody directed against the leptin receptor (LRAb) every two days during the feeding period. Panels F and G show identical treatments as for panels D and E demonstrating inhibition of STAT3 phosphorylation in hearts of animals treated with the LRAb. Quantitative data are presented as mean+SEM. N = 8 for myocyte data in panels A and C and N = 5 for data shown in panels E and G. *P<0.05 from respective control group (or H group in panels E and G); <sup>+</sup>P<0.05 from respective group in the absence of siFTO (-siFTO).</p
Hypertrophic responses to leptin with FTO, CUX1 and cathepsin L (Cath L) inhibition.
No full text<p>Cell surface area is shown in the left row whereas expression of ANP and β-MHC are depicted in the middle and right rows, respectively. Note that the hypertrophic responses to leptin were abolished by all treatments. Data are presented as mean+SEM. N = 7. *P<0.05 from respective control values. <sup>+</sup>P<0.05 from the leptin alone group.</p
Suppression of CUX1 prevents leptin-induced FTO upregulation.
No full text<p>Immunofluorescent images and corresponding quantified immunofluorescence intensity data showing that CUX1 siRNA (+siCUX1) supressed basal FTO expression and completely prevented the effect of leptin on FTO. Quantitative data are presented as mean +SEM. N = 7. *P<0.05 from respective control group; <sup>+</sup>P<0.05 from respective group in the absence of siCUX1 (−siCUX1). Horizontal bar in bottom right images indicates 200 µm.</p
Upregulation of CUX1 by leptin.
No full text<p>Panels A and B show that leptin increases CUX1 immunofluorescence intensity in cultured cardiomyocytes. Panels C to E demonstrate representative Western blots (C) and corresponding quantitative data (D, E) documenting increased protein expression of p110 CUX 1 with a non-significant effect on the p200CUX1 isoform. The increase in p110 CUX protein levels was abolished by the cathepsin L inhibitory peptide (CLi). Quantitative data are presented as mean +SEM. N = 7. *P<0.05 from control; <sup>+</sup>P<0.05 from respective group in the absence of CLi (-CLi). Horizontal bar in bottom right images indicates 200 µm.</p
