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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy.

Details

Title
Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction
Author
Sayour, Nabil V 1 ; Tóth, Viktória É 1 ; Nagy, Regina N 2   VIAFID ORCID Logo  ; Vörös, Imre 1   VIAFID ORCID Logo  ; Gergely, Tamás G 1   VIAFID ORCID Logo  ; Onódi, Zsófia 1 ; Nagy, Noémi 3 ; Bödör, Csaba 3 ; Váradi, Barnabás 4 ; Ruppert, Mihály 5 ; Radovits, Tamás 5 ; Bleckwedel, Federico 6   VIAFID ORCID Logo  ; Zelarayán, Laura C 6 ; Pacher, Pal 7 ; Ágg, Bence 8   VIAFID ORCID Logo  ; Görbe, Anikó 9 ; Ferdinandy, Péter 8 ; Varga, Zoltán V 1   VIAFID ORCID Logo 

 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; [email protected] (N.V.S.); ; HCEMM-SU Cardiometabolic Immunology Research Group, 1085 Budapest, Hungary; MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, 1085 Budapest, Hungary 
 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; [email protected] (N.V.S.); 
 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary 
 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; [email protected] (N.V.S.); ; HCEMM-SU Cardiometabolic Immunology Research Group, 1085 Budapest, Hungary 
 Heart and Vascular Center, Semmelweis University, 1085 Budapest, Hungary 
 Institute of Pharmacology and Toxicology, University Medical Center Goettingen (UMG), 37075 Göttingen, Germany; German Center for Cardiovascular Research (DZHK) Partner Site, 37075 Goettingen, Germany 
 Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Rockville, MD 20852, USA 
 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; [email protected] (N.V.S.); ; MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; Pharmahungary Group, 6720 Szeged, Hungary 
 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; [email protected] (N.V.S.); ; Pharmahungary Group, 6720 Szeged, Hungary 
First page
13826
Publication year
2023
Publication date
2023
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2869385132
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.