Pacing-Induced Regional Differences in Adenosine Receptors mRNA Expression in a Swine Model of Dilated Cardiomyopathy

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

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Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors

Behavioural Brain Research ◽

10.1016/j.bbr.2014.07.006 ◽

2014 ◽

Vol 272 ◽

pp. 252-263 ◽

Cited By ~ 12

Author(s):

Peter J. Clark ◽

Parsa R. Ghasem ◽

Agnieszka Mika ◽

Heidi E. Day ◽

Jonathan J. Herrera ◽

...

Keyword(s):

Mrna Expression ◽

Adenosine Receptors ◽

Wheel Running ◽

Dorsal Striatum ◽

Uncontrollable Stress

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.BETA.1 and .BETA.2 Adrenoceptor Ligand and mRNA Expression in Dilated Cardiomyopathy.

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.18.1430 ◽

1995 ◽

Vol 18 (10) ◽

pp. 1430-1434 ◽

Cited By ~ 1

Author(s):

Christer SYLVEN ◽

Gunilla MISCHA ◽

Eva JANSSON ◽

Peter SOTONYI ◽

LiangXiong FU ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Mrna Expression ◽

Beta 2

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Regional differences in the ability of caffeine to affect haloperidol-induced striatal c-fos mRNA expression in the rat

Neuropharmacology ◽

10.1016/s0028-3908(98)00045-8 ◽

1998 ◽

Vol 37 (3) ◽

pp. 331-337 ◽

Cited By ~ 13

Author(s):

Per Svenningsson ◽

Ricard Nergårdh ◽

Bertil B Fredholm

Keyword(s):

Mrna Expression ◽

Regional Differences

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Assessment of Cardiac Fiber Orientation, Function, and Morphology in a Swine Model of Dilated Cardiomyopathy Using MRI

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2010.06.086 ◽

2010 ◽

Vol 16 (8) ◽

pp. S26

Author(s):

Michael D. Eggen ◽

Michael G. Bateman ◽

Christopher D. Rolfes ◽

Stephen A. Howard ◽

Cory M. Swingen ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Fiber Orientation ◽

Swine Model ◽

Orientation Function ◽

Cardiac Fiber

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Abstract 18845: Left Ventricular Assist Device Normalizes Multiple Pathogenic Pathways in Both the Left and Right Ventricle in Patients With Dilated Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.18845 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Nirmal Parajuli ◽

Ratnadeep Basu ◽

Konrad S Famulski ◽

Jayan Nagendran ◽

Daniel H Kim ◽

...

Keyword(s):

Right Ventricle ◽

Dilated Cardiomyopathy ◽

Mrna Expression ◽

Left Ventricular Assist Device ◽

Ventricular Assist Device ◽

Left Ventricular ◽

Assist Device ◽

Ventricular Assist ◽

Common Cause ◽

Left Ventricular Assist

Introduction: Heart failure (HF) continues to be a common cause of morbidity and mortality and dilated cardiomyopathy (DCM) is a common cause of adverse ventricular remodeling and HF. Left ventricular assist device (LVAD) has emerged as an important mode of therapy for advanced HF by unloading the LV and maintaining systemic perfusion. The extent to which LVAD mediates beneficial remodeling in the right ventricle (RV) is incompletely understood. Hypothesis: Differential mRNA expression in a chamber-specific manner may elucidate LVAD mediated functional reverse remodeling in end-stage HF. Methods and Results: Right (RV) and left (LV) ventricle tissue from explanted failing and non-failing control (NFC) human hearts were collected within 20 mins of explantation. Global mRNA expression profiling in DCM patients without (n=8; 7M/1F; age 42-54 years; ejection fraction (EF): 17.5% (15-26%) and with (n= 8; 7M/1F; age 44-58 yrs; EF 15% (12.5-25.0%) LVAD (HeartMate II) was compared to NFC (n=6; age 39-56 yrs; 4M/2F). mRNA microarray was performed using Affymetrix PrimeView gene chips and evaluated using the Ingenuity Pathway Analysis ( IPA) program. LVAD use was associated with marked reduction of myocardial hypertrophy, interstitial fibrosis and apoptosis in both the LV and RV. The cleaved caspase-3 and Tunnel-positive cardiomyocytes were reduced in both RV and LV with LVAD. Total gene entities of 991 in the LV and 860 in the RV were differentially expressed in hearts with DCM without LVAD. LVAD use was independently associated with the altered regulation of 280 genes in the LV and 380 genes in the RV. The total up/down regulated genes involved in cardiac hypertrophy ranged from 20-60% and myocardial fibrosis ranged from 10-80% and were altered in both the RV and LV in response to LVAD therapy. In addition, 14-30% of the total apoptotic-related genes and 6-20 % of the cytokine-related genes were changed in both ventricles. Conclusions: LVAD reduced pathological hypertrophy and fibrosis in both LV and RV and is correlated with altered gene expression controlling adverse myocardial remodeling and fibrosis, apoptotic and inflammatory pathways. LVAD therapy represents a viable long-term therapy for HF patients and is associated with improved RV remodeling.

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Caffeine effects on AdoR mRNA expression in Drosophila melanogaster

Open Life Sciences ◽

10.1515/biol-2016-0034 ◽

2016 ◽

Vol 11 (1) ◽

pp. 244-249

Author(s):

Jacek Francikowski ◽

Bartosz Baran ◽

Anna Płachetka-Bożek ◽

Michał Krzyżowski ◽

Maria Augustyniak

Keyword(s):

Drosophila Melanogaster ◽

Mrna Expression ◽

Adenosine Receptors ◽

Fruit Fly ◽

Adult Survival ◽

Cellular Targets ◽

Early Stages ◽

Wide Range ◽

Adult Survival Rate ◽

Mrna Expression Levels

AbstractIn this study, we aimed to evaluate whether exposure to caffeine in the early stages of development affect AdoR mRNA expression levels in the fruit fly (Drosophila melanogaster) and how this will relate to the developmental success of flies. Adenosine receptors are seen as the most important biochemical targets of caffeine. Simultaneously adenosine signaling orchestrates the development and growth of insects. We demonstrate that AdoR mRNA expression in D. melanogaster is persistent from early stages till imago. Strong alterations in AdoR expression were observed in larvae that had been treated with caffeine. However, after the imaginal molt, the differences in AdoR expression between the insects from all of the test groups evened out despite a wide range of developmental success in the groups. Taken together, these results suggest that caffeine affects the expression of its cellular targets even from the early stages of fruit fly development and thus there is a significantly lower larvae-to-adult survival rate. Moreover, we also proved that the expression of AdoR undergoes a peculiar reset during the maturation of D. melanogaster despite the conditions in which larvae developed.

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